EP0594540B1 - Antiretrovirale Acyl-Verbindungen - Google Patents

Antiretrovirale Acyl-Verbindungen Download PDF

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Publication number
EP0594540B1
EP0594540B1 EP93810724A EP93810724A EP0594540B1 EP 0594540 B1 EP0594540 B1 EP 0594540B1 EP 93810724 A EP93810724 A EP 93810724A EP 93810724 A EP93810724 A EP 93810724A EP 0594540 B1 EP0594540 B1 EP 0594540B1
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Prior art keywords
phenyl
butyl
acid
amino
lower alkyl
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German (de)
English (en)
French (fr)
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EP0594540A1 (de
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Guido Dr. Bold
Alexander Dr. Fässler
Marc Dr. Lang
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Novartis AG
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Ciba Geigy AG
Novartis AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to new antiretroviral compounds, processes for their preparation of these compounds, pharmaceutical preparations with these compounds, these Compounds for use in a therapeutic procedure for the treatment of human or animal body and the use of these compounds for therapeutic Treatment of the human or animal body or for manufacture pharmaceutical preparations.
  • Retroviruses There are quite a number of illnesses that are known to exist through Retroviruses.
  • AIDS is caused by the retrovirus HIV (Human Immunodeficiency Virus ”) caused immune system disease. This disease affects WHO estimates that around 10 million people are spreading more and more and practically always leads to the death of the patient.
  • retrovirus HIV Human Immunodeficiency Virus
  • HIV Human Immunodeficiency Virus
  • the retroviral protease is a proteolytic enzyme that is active due to an Center present aspartate residue is counted among the aspartate proteases and in Multiplication cycle of a number of retroviruses in the maturation of new infectious virions contributes within infected cells.
  • HIV-1 and HIV-2 each have a region in their genome that encoded for a "gag protease".
  • This "gag protease” is correct for the proteolytic Cleavage of the precursor proteins responsible for the "Group Specific Antigens "(gag) coding genome sections emerge.
  • the structural proteins of the virus core English “Core”, released.
  • the "gag protease” itself is Part of a precursor protein encoded by the pol genome section of HIV-1 and HIV-2, that also includes the sections for "reverse transcriptase” and "integrase” contains and is presumably autoproteolytically cleaved.
  • the "gag protease” cleaves the major core protein p24 of HIV-1 and HIV-2 preferably N-terminal from proline residues, e.g. B. in the bivalent radicals Phe-Pro, Leu-Pro or Tyr-Pro. It is a protease with a catalytic active aspartate residue in the active center, a so-called aspartate protease.
  • retroviral gag proteases especially the gag protease of HIV-1 (HIV-1 protease), but also against those of HIV-2 or other AIDS viruses.
  • the main goal at the moment is to provide such connections, the best possible have pharmacokinetic properties.
  • the prerequisite for therapeutic effectiveness in vivo is namely the achievement of good bioavailability, e.g. B. a good resorbability and / or a high blood level, even with enteral, such as oral administration, so as to reach sufficiently high concentrations on the infected cells, and / or a favorable distribution in the organism.
  • the object of the present invention is to provide structurally new ones antiretroviral active compounds with improved pharmacodynamic properties, which preferably have better absorption than the corresponding unmodified ones antiretroviral compounds even in enteral, especially oral, Administration show and / or blood levels especially of the unmodified antiretroviral lead active substance, which are higher than that with appropriate administration of the unmodified antiretroviral active substances themselves achievable.
  • the compounds according to the invention are those of the formula I wherein R 1 is acyl, and salts thereof.
  • EP 0 432 695 published on June 19, 1991
  • the compound of formula II which is also included generically in EP 0 346 847 (published on June 19, 1991) and for which a synthetic route is described in EP 0 432 694 (published on December 11, 1989).
  • This compound is also mentioned in the publications listed below and is examined, for example, for its activity in vitro, on cell cultures and in vivo and for structure / activity relationships: Tucker, TJ, et al., J. Med. Chem. 35 , 2525-2533 ( 1992); Roberts, NA, et al., Biochem. Soc. Transact. 20 , 513-516 (1992); Krausslich, H.-G., J.
  • the compounds of the formula I according to the invention can exist in different isomeric forms if the radical R 1 can exist in different isomeric forms.
  • asymmetric carbon atoms present in the substituents R 1 can be present independently of one another in the (R), (S) or (R, S) configuration, and / or cis / trans isomerism can occur on multiple bonds, such as double bonds.
  • the compounds of the formula I can be present as mixtures of isomers, in particular as mixtures of diastereomers or as racemates, or as pure isomers, in particular as pure enantiomers.
  • lower alkyl means that the groups or residues defined in this way, unless explicitly defined otherwise, up to and including 7 and preferably up to and including Contain 4 carbon atoms.
  • Lower alkenyl and lower alkynyl means “Lower” means the presence of at least 2 to a maximum of 7, preferably of 2 to 4, carbon atoms, in the case of lower alkenoyl or lower alkynoyl 3 to 7, preferably 3 or 4 carbon atoms.
  • Acyl R 1 has, for example, up to 25, preferably up to 19 carbon atoms, and is primarily the acyl group of a carboxylic acid or an unsubstituted or substituted amino acid bonded via its carbonyl, furthermore aminocarbonyl or the residue of an N-substituted bond bonded via its aminocarbonyl group Carbamic acid or the residue of a half-ester of carbonic acid bound via carbonyl.
  • Preferred acyl groups R 1 of a carboxylic acid are, for example, unsubstituted alkanoyl, alkenoyl or alkinoyl, or substituted alkanoyl, alkenoyl or alkinoyl, in particular octanoyl, decanoyl, dodecanoyl, or palmitoyl, unsubstituted or substituted lower alkanoyl, lower alkenyl, for example, or a lower alkynoyl or lower alkynoyl Residues, preferably from up to three residues, in particular from one residue or two residues selected from the group hydroxyl, lower alkoxy, lower alkoxy lower alkoxy, lower alkoxy lower alkoxy lower alkoxy, phenoxy, naphthoxy, phenyl lower alkoxy, 2-halogeno lower alkanoyl, such as 2-chloroacetyl, amino, lower alkylamino or di-lower lower alk
  • pyrrolyl, 2,5-dihydropyrrolyl, furanyl, thienyl, tetrahydrofuranyl, cyclohepta [b] pyrrolyl, pyrrolidinyl, imidazolyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, triazolyl, such as 1,2,3-, 1,2,4- or 1 , 3,4-triazolyl, tetrazolyl, such as 1- or 2-tetrazolyl, tetrahydro-oxazolyl, tetrahydro-isoxazolyl, tetrahydro-thiazolyl, tetrahydro-isothiazolyl, indolyl, isoindolyl, quinolyl, isoquinolyl, benzimiduridylylidylylidylylidylyl , Piperazin-1-yl, morpholino, thio,
  • methylcarbamoylacetyl or ⁇ - (N-lower alkyl) carbamoylpropionyl such as ⁇ - (N-methyl) -, ⁇ - (N-ethyl) -, ⁇ - (N- (n-propyl)) - carbamoyl- or ⁇ - (N- (n-Hexyl)) - carbamoylpropionyl, di-lower alkylcarbamoyl-lower alkanoyl, e.g.
  • dimethylcarbamoylacetyl ⁇ - (N, N- (di-lower alkyl) -carbamoyl) propionyl, such as ⁇ - (N, N-dimethyl) -, ⁇ - (N , N-Diethyl) -, ⁇ - (N, N-Di- (n-propyl) -carbamoyl) - or ⁇ - (N, N-Di- (n-hexyl)) - carbamoylpropionyl, ⁇ -pyrrolidinocarbonylpropionyl, ⁇ - Morpholinocarbonylpropionyl, ⁇ -thiomorpholinocarbonylpropionyl, ⁇ -piperidin-1-ylcarbonypropionyl, ⁇ -piperazin-1-ylcarbonylpropionyl or ⁇ - (4-lower alkyl-piperazin-1-ylcarbonyl) propionyl, such as ⁇ -
  • 2-pyridylacetyl, or pyridylpropyl eg 3- (2-pyridyl) propionyl, quinolylcarbonyl, such as quinolin-2-ylcarbonyl, isoquinolinecarbonyl, such as isoquinolin-3-ylcarbonyl, optionally substituted indolylcarbonyl, for example 2-, 3- or 5-indolylcarbonyl, 1-methyl-, 5- Methyl, 5-methoxy, 5-benzyloxy, 5-chloro or 4,5-dimethylindolyl-2-carbonyl, cyclohepta [b] pyrrolyl-5-carbonyl, pyrrolidine (2- or 3-) yl-carbonyl (where pyrrolidinyl-2-carbonyl ( prolyl) is preferably in the D or L form), hydroxypyrrolidinylcarbonyl, for example 3- or 4-hydroxypyrrolidinyl-2-carbonyl, oxopyrrol
  • Preferred acyl groups R 1 of a half ester of carbonic acid are, for example, unsubstituted or substituted alkyloxycarbonyl, in particular lower alkoxycarbonyl, for example methoxy-, ethoxy- or tert-lower alkoxycarbonyl, such as tert-butoxycarbonyl, 2-halogeno lower alkoxycarbonyl, for example 2-chloro, 2-bromo, 2 Iodine or 2,2,2-trichloroethoxycarbonyl;
  • Aryl-lower alkoxycarbonyl for example arylmethoxy-carbonyl, in which aryl preferably has 6 to 14 carbon atoms, unsubstituted or for example by lower alkyl, for example methyl, halogen-lower alkyl, such as chloromethyl or bromomethyl, halogen, for example fluorine or chlorine, hydroxy, lower alkoxy, such as methoxy, lower alkanoyloxy, carboxy , Lower
  • a preferred acyl group R 1 of an N-substituted carbamic acid is an aminocarbonyl radical, in which the amino group bears 1 to 2 substituents which are independently selected from unsubstituted or substituted lower alkyl, the substituents of which are selected from those mentioned above for substituted lower alkanoyl and are present in the number defined there can, preferably substituents selected from hydroxy, lower alkoxy, phenoxy, naphthoxy, lower alkanoyloxy, phenyl-lower alkanoyloxy, such as benzoyloxy or phenylacetyloxy, halogen, such as fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine, carboxy, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, carbam Lower alkyl carbamoyl, hydroxy lower alkyl carbamoyl, di lower alkyl carbamoyl
  • Preferred acyl groups R 1 of an unsubstituted or substituted amino acid are formed by the amino acid residues of an ⁇ , ⁇ , ⁇ or ⁇ amino acid bonded via their carbonyl group, in particular a natural ⁇ -amino acid with the L configuration as normally found in proteins, or an epimer of such an amino acid, ie with the unnatural D configuration, or its D, L isomer mixture, a homologue of such an amino acid, e.g. B.
  • a substituted aromatic amino acid in which the aromatic radical 6 - has 14 carbon atoms, e.g. B. a substituted phenylalanine or phenylglycine, wherein the phenyl substituent is lower alkyl, e.g. B. methyl, hydroxy, lower alkoxy, e.g. B. methoxy, lower alkanoyloxy, e.g. B. acetoxy, amino, lower alkylamino, e.g. B.
  • methylamino, di-lower alkylamino e.g. B. Dimethylamino, Niederalkanoylamino, z. B. acetylamino or pivaloylamino, lower alkoxycarbonylamino, e.g. B. tert-butoxycarbonylamino, arylmethoxycarbonylamino, wherein aryl preferably has 6 - 14 carbon atoms, e.g. B. benzyloxycarbonylamino or 9-fluorenylmethoxycarbonylamino, halogen, e.g. B.
  • a benzannelated phenylalanine or phenylglycine such as ⁇ -naphthylalanine
  • a hydrogenated phenylalanine or phenylglycine such as cyclohexylalanine or cyclohexylglycine.
  • acyl groups of amino acids such as prolyl, indoline-2-carbonyl, 1,2,3,4-tetrahydroisoquinoline-3-carbonyl and trans-3 and trans-4-hydroxyprolyl, which are already mentioned in the definition of substituted Niederalkanoyl R 1 occur, except, but only with the sole purpose of avoiding the overlap of the definitions.
  • amino acid residues can on free amino or hydroxy functions, preferably on a free amino function, by one of the radicals mentioned above under acyl R 1 as an acyl group of a carboxylic acid or a half ester of carbonic acid, by unsubstituted or substituted alkyl, especially lower alkyl, such as methyl, ethyl, Isopropyl, n-propyl or n-butyl, in which the substituents are selected, for example, from one or more residues, preferably from up to three residues, in particular from one residue selected from the group consisting of hydroxyl, lower alkoxy, phenoxy, naphthoxy, lower alkanoyloxy, halogen, such as fluorine, Chlorine, bromine or iodine, in particular fluorine or chlorine, carboxy, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, carbamoyl, lower alky
  • octen-2-yl, heterocyclyl which is a saturated, partially saturated or unsaturated ring which is present as such or in mono- or doubly, in particular mono-, benz-, cyclopenta-, cyclohexa- or cyclohepta-fused form, of the 3 to 7 , preferably 5-7 ring atoms and contains up to four heteroatoms selected from nitrogen, sulfur and / or oxygen, preferably 1 or 2 of the heteroatoms mentioned, and unsubstituted or, in particular by lower alkyl, lower alkanoyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, such as benzyloxy, Hydroxy-lower alkyl, such as hydroxymethyl, halogen, cyano and / or trifluoromethyl, may be substituted can means z.
  • pyrrolyl, 2,5-dihydropyrrolyl, furanyl, thienyl, tetrahydrofuranyl, cyclohepta [b] pyrrolyl, pyrrolidinyl, imidazolyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, triazolyl, such as 1,2,3-, 1,2,4-or 1 , 3,4-triazolyl, tetrazolyl, such as 1- or 2-tetrazolyl, tetrahydro-oxazolyl, tetrahydro-isoxazolyl, tetrahydro-thiazolyl, tetrahydro-isothiazolyl, indolyl, isoindolyl, quinolyl, isoquinolyl, benzimiduridylylidylylidylylidylyl , Piperazin-1-yl, morpholino, thio,
  • 4-lower alkyl-piperazin-1-yl such as 4-methyl or 4-ethyl-piperazin-1-yl, or by lower alkanoyl, e.g.
  • 4-lower alkanoylpiperazin-1-yl such as 4-acetyl-piperazin-1-yl
  • aryl preferably C 6 -C 12 aryl, for example phenyl, naphthyl such as 1- or 2-naphthyl, indanyl such as 1- or 2-indanyl, indenyl such as inden-1-yl, or fluorenyl such as fluorene 9-yl, the aryl radicals mentioned being unsubstituted or, for example, by lower alkyl, for example methyl, halogen-lower alkyl, such as chloromethyl or bromomethyl, halogen, for example fluorine or chlorine, hydroxy, lower alkoxy, such as methoxy, lower alkanoyloxy,
  • the radical of an amino acid bonded via the carbonyl group is particularly preferably selected from glycine (H-Gly-OH), alanine (H-Ala-OH), 2-aminobutyric acid, 3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid , 5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid or 5-aminohexanoic acid, valine (H-Val-OH), norvaline ( ⁇ -aminovaleric acid), leucine, (H-Leu-OH), isoleucine (H-Ile-OH ), Norleucine ( ⁇ -aminohexanoic acid, H-Nle-OH), serine (H-Ser-OH), homoserine ( ⁇ -amino- ⁇ -hydroxybutyric acid), threonine (H-Thr-OH), methionine (H-
  • lower alkyl such as methyl, n-propyl or n-butyl
  • amino-lower alkyl such as 3-aminopropyl
  • phenyl or naphthylamino-lower alkyl such as 3-phenylaminopropyl
  • phenyl-lower alkyl such as benzyl
  • diphenylmethyl by trityl, and / or by heterocyclyl-lower alkyl
  • heterocylcyl is as defined above for an acyl group R 1 of a carboxylic acid, in particular by heterocyclylmethyl, for example furanyl-lower alkyl, such as 2-furylmethyl, thienyl-lower alkyl, such as 2-thienylmethyl, imidazolyl-lower alkyl, such as imidazole-2-3-almethyl - or 4-pyridyl-lower alkyl, such as 2-, 3- or 4-pyridyl-lower alkyl
  • acyl groups of a carboxylic acid mentioned above in the definition of R 1 in particular by unsubstituted or substituted lower alkanoyl, as defined above, especially by acetyl, propionyl, pivaloyl, heterocyclyl-lower alkanoyl, as defined above for acyl R 1 , for example furan-2 -ylcarbonyl, 5-hydroxymethyl-furan-2-ylcarbonyl, 2-, 3- or 4-pyridylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, indolylacetyl or benzofuranylacetyl, aryl-lower alkanoyl, such as benzoyl or phenylacetyl, or the acyl groups mentioned above for the definition of R 1 Half ester of carbonic acid, especially lower alkoxycarbonyl, such as tert-butoxycarbonyl, or aryl-lower alkoxycarbonyl, such as
  • B as a lower alkyl ester group, such as methoxycarbonyl or tert-butoxycarbonyl, as an aryl ester group or as an aryl lower alkyl ester group, in which aryl is phenyl, 4-nitrophenyl, naphthyl, fluorenyl or biphenylyl, e.g. B.
  • carbamoyl as 4-nitrophenyloxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl, or as carbamoyl, as lower alkylcarbamoyl, such as methylcarbamoyl, as di-lower alkylcarbamoyl, such as dimethylcarbamoyl, as mono- or di- (hydroxy-lower alkyl) carbamoyl, such as hydroxymethylcarbamoyl Di- (hydroxymethyl) carbamoyl, or as mono- or di- (carboxy-lower alkyl) carbamoyl, such as carboxymethylcarbamoyl or di- (carboxymethyl) carbamoyl group, an amino group of the side chain, which is not in the ⁇ -position, free or in alkylated form, e.g.
  • B. as mono- or di-lower alkylamino, such as n-butylamino or dimethylamino, or in acylated form, for.
  • B. as lower alkanoylamino, such as acetylamino or pivaloylamino, as amino lower alkanoylamino, such as 3-amino-3,3-dimethylpropionylamino, as aryl lower alkanoylamino, wherein aryl has 6 - 14 carbon atoms, e.g. B.
  • phenyl, naphthyl or fluorenyl is phenyl, naphthyl or fluorenyl, and is unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, carboxy, carbamoyl or sulfamoyl, such as 4-hydroxyphenylbutyryl, as lower alkoxycarbonylamino, such as tert-butoxycarbonylamino, as arylmethoxycarbonylamino, in which aryl has 6-14 carbon atoms , as as benzyloxycarbonylamino or 9-fluorenylmethoxycarbonylamino, as piperidyl-1-carbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or as S, S-dioxothiomorpholinocarbonyl, and / or a hydroxy group of the side chain free, in etherified or esterified form, e.g.
  • acyl groups R 1 of an unsubstituted or substituted amino acid are selected from alanyl, N-lower alkylalanyl, such as N-methylalanyl, phenylalanyl, N- (benzyloxycarbonyl) phenylalanyl, N- (9-fluorenylmethoxycarbonyl) phenylalanyl, aminoacetyl (glycyl), N-lower alkylamino , N, N-di-lower alkylaminoacetyl, N-lower alkyl-N-phenyl-lower alkylaminoacetyl, N-lower alkyl-N-imidazolyl-lower alkylaminoacetyl, N-lower alkyl-N-pyridyl-lower alkylaminoacetyl, N-lower alkyl-N-lower alkoxycarbonylaminoacetyl, N-phenyl-lower
  • hydroxyl or amino groups which have a free hydrogen atom are on a carbon atom from which a double bond originates, for example in the case of substituted lower alkenyl or lower alkynyl, in compounds of the formula I, tautomeric forms (by keto / enoltautomerism or imine / enamineautomerism) ) possible.
  • tautomeric forms by keto / enoltautomerism or imine / enamineautomerism
  • Salts of compounds of the formula I are, in particular, acid addition salts, salts with Bases or, if there are several salt-forming groups, optionally also mixed salts or inner salts.
  • Salts are primarily the pharmaceutically acceptable, non-toxic salts of Compounds of formula I.
  • Such salts are used, for example, by compounds of the formula I with an acidic one Group, e.g. B. a carboxy group, and are, for example, the salts thereof suitable bases, such as non-toxic, of Group Ia, Ib, IIa and IIb metals Periodic table of the elements derived metal salts, primarily suitable Alkali metal, e.g. B. lithium, sodium or potassium, or alkaline earth metal salts, e.g. B.
  • N-methyl-N-ethylamine Diethylamine, triethylamine, mono-, bis- or tris- (2-hydroxy-lower alkyl) amines, such as mono-, bis- or tris- (2-hydroxyethyl) amine, 2-hydroxy-tert-butylamine or tris (hydroxymethyl) methylamine, N, N-di-lower alkyl-N- (hydroxy-lower alkyl) amines, such as N, N-dimethyl-N- (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, N-methyl-D-glucamine or quaternary ammonium salts such as tetrabutylammonium salts.
  • the compounds of formula I with a basic group can form acid addition salts, for example with inorganic Acids, e.g. B. hydrohalic acid, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic, sulfonic, sulfonic or phosphonic acids or N-substituted Sulfamic acids such as B.
  • inorganic Acids e.g. B. hydrohalic acid, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic, sulfonic, sulfonic or phosphonic acids or N-substituted Sulfamic acids such as B.
  • the compounds of formula I have valuable pharmacological properties. After application to a warm-blooded animal, such as humans, they are metabolically released from compounds of the formula II, which are described as antiretroviral inhibitors of aspartate proteases, such as HIV protease, and in particular for the treatment of AIDS as inhibitors of aspartate proteases of HIV- 1 and / or HIV-2 (and possibly other retroviruses which cause symptoms similar to AIDS) are suitable (see EP 0 346 847 (published on June 19, 1991) and the other publications mentioned above).
  • the binding of the compound of formula II to HIV-1 protease is described, for example, in J. Med. Chem.
  • the compounds of formula II are in the body of the animal to be treated, preferably a warm-blooded animal, including a human, from the compounds of Formula I released.
  • the advantageous pharmacodynamic properties can be as follows, for example be occupied:
  • the compounds of formula I to be examined or, as a control, the comparison compound of formula II are in dimethyl sulfoxide (DMSO) in a concentration of 240 mg / ml.
  • DMSO dimethyl sulfoxide
  • HP ⁇ CD hydroxypropyl- ⁇ -cyclodextrin
  • the blood is heparinized and for analysis by one of the following Both methods prepared: After the first method, whole blood is deproteinized by mixing a volume of blood with a volume of acetonitrile; after centrifugation the supernatant is examined by reversed phase HPLC. After the second Method becomes an internal standard for heparinized blood at a final concentration of 4 ⁇ M added. The blood is centrifuged. 0.25 ml of plasma are removed and deproteinized with an equal volume of acetonitrile. After centrifugation, the The supernatant dried in vacuo and the residue in 20 ul 3M NaCl solution and 100 ⁇ l of 0.05M phthalate buffer with a pH of 3.0 suspended.
  • the suspension is only extracted with 1 ml, then with 0.2 ml of diisopropyl ether.
  • the diisopropyl ether solution becomes evaporated to dryness and the residue dissolved in 50% (v / v) aqueous acetonitrile. This solution is examined by reversed phase HPLC.
  • the concentration of the active component of the formula II in the blood of mice is after oral administration of a compound of the formula I, for example the compound of the formula I, wherein R 1 is acetyl, at most times, preferably at all times mentioned above, significantly higher than when the compound of the formula II is administered in unesterified form, for example more than three times as high.
  • the absorption of the compound of formula I for example that in which R 1 is acetyl, is significantly higher than the absorption of the compound of formula II, for example more than four times as high. It is also possible to obtain a higher blood level with a compound of the formula I for a longer period than with the compound of the formula II.
  • the compounds of the present invention can also find use as commercial commercially available reference substances when testing other aspartate protease inhibitors, by practically using them as standard substances, e.g. with others animal species used to have a measure of the extent to which blood levels obtained from depend on the animal species.
  • a connection not mentioned here can be used the above-mentioned mouse model are examined, on the other hand one mentioned here Compound of formula I as a comparison substance in comparison with that to be examined Compound can be used with other animal models.
  • Preferred compounds of the formula I are those in which R 1 is octanoyl, decanoyl, dodecanoyl, palmitoyl, unsubstituted or substituted lower alkanoyl, lower alkenyl or lower alkynoyl, in which the substituents consist of one or more radicals, preferably of up to three radicals, in particular of one radical or two further Radicals selected from the group consisting of hydroxy, lower alkoxy, lower alkoxy lower alkoxy, lower alkoxy lower alkoxy lower alkoxy, phenoxy, naphthoxy, phenyl lower alkoxy, 2-halogeno lower alkanoyl, such as 2-chloroacetyl, amino, lower alkylamino or diniederalkylamino lower alkoxy-2-lower alkaminoyl, such as dimoxy Lower alkylamino or di-lower alkylamino-lower alkoxy-lower alkoxy-2-lower alkano
  • pyrrolyl, 2,5-dihydropyrrolyl, furanyl, thienyl, tetrahydrofuranyl, cyclohepta [b] pyrrolyl, pyrrolidinyl, imidazolyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, triazolyl, such as 1,2,3-, 1,2,4- or 1 , 3,4-triazolyl, tetrazolyl, such as 1- or 2-tetrazolyl, tetrahydro-oxazolyl, tetrahydro-isoxazolyl, tetrahydro-thiazolyl, tetrahydro-isothiazolyl, indolyl, isoindolyl, quinolyl, isoquinolyl, benzimiduridylylidylylidylylidylyl , Piperazin-1-yl, morpholino, thio,
  • R 1 is aminocarbonyl or an aminocarbonyl radical, in which the amino group bears 1 to 2 substituents which, independently of one another, consist of unsubstituted or substituted lower alkyl, the substituents of which are hydroxy, lower alkoxy, Phenoxy, naphthoxy, lower alkanoyloxy, phenyl-lower alkanoyloxy, such as benzoyloxy or phenylacetyloxy, halogen, such as fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine, carboxy, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, carbamoyl, lower alkylcarbamoyl, hydroxyniederalkyl
  • R 1 is unsubstituted or substituted lower alkanoyl, lower alkenyl or lower akinoyl, in which the substituents consist of one or more radicals, preferably up to three radicals, in particular one radical selected from the group consisting of hydroxyl, lower alkoxy and phenoxy, Naphthoxy, lower alkanoyloxy, phenyl-lower alkanoyloxy, such as benzoyloxy or phenylacetyloxy, halogen, such as fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine, carboxy, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, carbamoyl, lower alkylcarbamoyl, hydroxyniederalkylcarbamoyloyl, hydroxyl-lower alkylcarbamoyloyl, carb
  • pyrrolyl, 2,5-dihydropyrrolyl, furanyl, thienyl, tetrahydrofuranyl, cyclohepta [b] pyrrolyl, pyrrolidinyl, imidazolyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, triazolyl, such as 1,2,3-, 1,2,4- or 1 , 3,4-triazolyl, tetrazolyl, such as 1- or 2-tetrazolyl, tetrahydro-oxazolyl, tetrahydro-isoxazolyl, tetrahydro-thiazolyl, tetrahydro-isothiazolyl, indolyl, isoindolyl, quinolyl, isoquinolyl, benzimiduridylylidylylidylylidylyl , Piperazin-1-yl, morpholino, thio,
  • 4-lower alkyl-piperazin-1-yl such as 4-methyl or 4-ethyl-piperazin-1-yl
  • lower alkanoyl e.g. B. in 4-lower alkanoyl-piperazin-1-yl, such as 4-acetyl-piperazin-1-yl, or by hydroxy-lower alkyl, for example in 5-hydroxymethyl-furan-2-ylcarbonyl, and C 6 -C 12 aryl, for example Phenyl, naphthyl, such as 1- or 2-naphthyl, indanyl, such as 1-or 2-indanyl, indenyl, such as inden-1-yl, or fluorenyl, such as fluoren-9-yl, in which aryl is unsubstituted or, for example, by lower alkyl, for example Methyl, halogen-lower alkyl, such as chloromethyl or bromomethyl, halogen, for example fluoren-9-
  • R 1 is aminocarbonyl or an aminocarbonyl radical, in which the amino group bears 1 to 2 substituents which, independently of one another, consist of unsubstituted or substituted lower alkyl, the substituents of which are hydroxy, lower alkoxy, Phenoxy, naphthoxy, lower alkanoyloxy, phenyl-lower alkanoyloxy, such as benzoyloxy or phenylacetyloxy, halogen, such as fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine, carboxy, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, carbamoyl, lower alkylcarbamoyl, hydroxyniederalkyl
  • R 1 is octanoyl, decanoyl, dodecanoyl, palmitoyl, unsubstituted or substituted lower alkanoyl, in which the substituents are selected from one or up to three radicals, in particular from one radical or from two radicals selected from the group hydroxyl, lower alkoxy , Niederalkoxyniederalkoxy, Niederalkoxyniederalkoxy-Niederalkoxy, Phenoxy, Naphthoxy, Phenylniederalkoxy, 2-Halogiederiederalkanoyl, such as 2-chloroacetyl, amino, Niederalkylamino- or Diniederalkylamino-Niederalkoxy-2-Niederalkanoyl, such as Dimethylamino-Niederalkoxy-Niederalk- alkoxyaminoaminoam, amino -2-lower alkanoyl, such as di
  • 4-lower alkyl-piperazin-1-yl such as 4-methyl or 4-ethyl-piperazin-1-yl
  • lower alkanoyl for example in 4-lower alkanoylpiperazin-1-yl, such as 4-acetyl-piperazin-1 -yl, or by hydroxy-lower alkyl, for example in 5-hydroxymethyl-furan-2-ylcarbonyl, and aryl selected from phenyl, naphthyl, such as 1- or 2-naphthyl, indanyl, such as 1- or 2-indanyl, indenyl, such as indene 1-yl and fluorenyl, such as fluoren-9-yl, these radicals being unsubstituted or, for example, by lower alkyl, for example methyl, halogen-lower alkyl, such as chloromethyl or bromomethyl, halogen, for example fluorine or chlorine, hydroxy, lower alkoxy, such as meth
  • rpholinomethyl, thiomorpholinomethyl, cyano and / or nitro are substituted one or more times, preferably monosubstituted, in particular phenyl, which is substituted in the p-position by one of the radicals mentioned, or the radical of an amino acid bound via the ⁇ -carbonyl group is selected from glycine, alanine, 2-aminobutyric acid, 3-aminobutyric acid, 4-aminobutyric acid, 3-aminopentanoic acid, 4-aminopentanoic acid, 5-aminopentanoic acid, 3-aminohexanoic acid, 4-aminohexanoic acid, 5-aminohexanoic acid, valine, norvaline, leucine, isoleucine, norleucine , Serine, homoserine, threonine, methionine, cysteine, phenylalanine, tyrosine, 4-aminophenylalan
  • R 1 is unsubstituted or substituted lower alkanoyl, in which the substituents consist of one or up to three radicals, in particular one radical selected from the group consisting of hydroxyl, lower alkoxy, phenoxy, naphthoxy, lower alkanoyloxy, phenyl-lower alkanoyloxy, such as benzoyloxy or phenylacetyloxy, halogen, such as fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine, carboxy, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, carbamoyl, lower alkylcarbamoyl, hydroxy-lower alkylcarbamoyl, di-lower alkylcarbamoyl, bis (hydroxy-lower alkyl) carbamoyl, C 3 -C 8, oxano, o
  • 4-lower alkyl-piperazin-1-yl such as 4-methyl or 4-ethyl-piperazin-1-yl
  • lower alkanoyl for example in 4-lower alkanoyl-piperazin-1-yl, such as 4-acetyl-piperazine -1-yl, or by hydroxy-lower alkyl, for example in 5-hydroxymethyl-furan-2-ylcarbonyl, and aryl selected from phenyl, naphthyl, such as 1- or 2-naphthyl, indanyl, such as 1- or 2-indanyl, indenyl, such as Inden-1-yl, and fluorenyl, such as fluoren-9-yl, these radicals being unsubstituted or, for example, by lower alkyl, for example methyl, halogen-lower alkyl, such as chloromethyl or bromomethyl, halogen, for example fluorine or chlorine, hydroxy, lower alkoxy, such as
  • R 1 is octanoyl, decanoyl, dodecanoyl, palmitoyl, lower alkanoyl, such as formyl, acetyl, propionyl, butyryl, methylpropionyl, n-pentanoyl, pivaloyl, hexanoyl or heptanoyl, hydroxy-lower alkanoyl, for example, ⁇ -hydroxypropyl Lower alkoxy lower alkanoyl, for example lower alkoxyacetyl or lower alkoxypropionyl, such as methoxyacetyl, 3-methoxypropionyl or n-butyloxyacetyl, lower alkoxyniederylkoxyniederalkanoyl, such as 2- (2-methoxyethoxy) acetyl, lower alkoxyniederalkoxyniederalkoxyniederalkanyl (meth) acetyl, lower alk
  • R 1 is lower alkanoyl, such as acetyl, propionyl, butyryl, pivaloyl, hexanoyl or heptanoyl, Hydroxyniederalkanoyl such as ⁇ -hydroxypropionyl, Niederalkoxyniederalkanoyl such Niederalkoxyacetyl or Niederalkoxypropionyl as methoxyacetyl or ⁇ -methoxypropionyl, Phenoxyniederalkanoyl , for example phenoxyacetyl, lower alkanoyloxy lower alkanoyl, for example lower alkanoyloxyacetyl or lower alkanoyloxypropionyl, such as acetoxyacetyl or oxo-lower alkanoyl, for example acetoacetyl or propionylacetyl, 5-hydroxymethyl-furan-2-ylcarbonyl, carbonyl,
  • R 1 is octanoyl, decanoyl, dodecanoyl, palmitoyl, lower alkanoyl, such as acetyl, propionyl, butyryl, methylpropionyl, n-pentanoyl, pivaloyl, hexanoyl or heptanoyl, lower alkoxy lower alkanoyl, or 4-methoxyacetyl, such as methoxyacetyl, are particularly preferred -Butoxyacetyl, lower alkoxy lower alkoxy lower alkanoyl, such as 2- (2-methoxyethoxy) ethoxyacetyl, lower alkoxy lower alkoxy lower alkanoyl, such as 2- (2- (2-methoxyethoxy) ethoxy) acetyl, phenoxy lower alkanoyl, such as phenoxyacetyl, phenyl lower alkoxy lower alkanoyl, such as phenoxyace
  • R 1 is lower alkanoyl, such as acetyl, propionyl, butyryl, pivaloyl, hexanoyl or heptanoyl, furylcarbonyl, for example furan-2-ylcarbonyl, pyridylcarbonyl, for example 2-, 3- or 4-pyridylcarbonyl, phenyl-lower alkanoyl , e.g.
  • R 1 is lower alkanoyl, such as acetyl, lower alkoxy lower alkanoyl, such as methoxyacetyl, pyridylcarbonyl, such as pyridin-2-ylcarbonyl, or furylcarbonyl, such as furan-2-ylcarbonyl, and pharmaceutically acceptable salts thereof are very particularly preferred.
  • R 1 is lower alkanoyl, such as acetyl, or furylcarbonyl, such as furan-2-ylcarbonyl, and pharmaceutically acceptable salts thereof are very particularly preferred.
  • R 1 is lower alkoxy-lower alkanoyl, such as methoxyacetyl or pyridylcarbonyl, such as pyridin-2-ylcarbonyl, and pharmaceutically acceptable salts thereof are also very particularly preferred.
  • An ester is prepared, for example, in a manner known per se using an acid of the formula III in which R 1 has the meanings mentioned, apart from aminocarbonyl or the rest of an N-substituted carbamic acid, or a reactive derivative thereof.
  • a reactive derivative is, for example, a compound of the formula IIIa R 1 -Z 1 into consideration, in which R 1 has the last-mentioned meanings and Z 1 in particular means reactively activated hydroxy.
  • the free carboxylic acid of the formula III can be, for example, strong acids, such as hydrogen halide, sulfur, sulfonic or carboxylic acid or acidic ion exchangers, for example hydrochloric, hydrobromic or hydroiodic acid, sulfuric acid, an alkane carboxylic acid which is optionally substituted, for example, by halogen, or by an acid of the formula III, preferably with an excess of the acid of the formula III, if necessary with binding of water of reaction formed by water-binding agents, with azeotropic distillation of the water of reaction or with extractive esterification, with acid anhydrides, in particular inorganic acid anhydrides such as carboxylic acid anhydrides such as lower alkane carboxylic acid anhydrides ( in addition to formic anhydride), for example acetic anhydride, or by suitable activation or coupling reagents of the type listed below, in particular also in situ.
  • strong acids such as hydrogen halide, sulfur, sulfonic or carboxylic
  • R 1 -Z 1 can also be used for a carboxylic acid azide (obtainable, for example, by reacting an appropriate acid ester with the corresponding hydrazide and treating it with nitrous acid); for a carboxylic acid halide, in particular an acid chloride or bromide, which, for example, by reaction with organic acid halides, in particular with oxalyldihalides, such as oxalyl dichloride, or especially with inorganic acid halides, for example with acid halides of phosphorus or sulfur, such as phosphorus trichloride, phosphorus pentachloromide, Phosphorus oxychloride, phosphorus oxybromide, thionyl chloride or thionyl bromide, or above all under mild conditions with tetraniederalkyl- ⁇ -halogenamines, such as tetramethyl- ⁇ -halo-enamines, in particular 1-chloro-N, N, 2-trimethyl-1-prop
  • the acid halide obtained for example the acid chloride of the formula IIIa, in which Z 1 is chlorine
  • the acid halide of the formula IIIa in which Z 1 is chlorine
  • tertiary nitrogen bases such as Pyridine and / or 4-dimethylaminopyridine (DMAP, which is preferably added in catalytic amounts)
  • DMAP 4-dimethylaminopyridine
  • Z 1 is in particular cyanomethoxy, nitrophenoxy, such as 4-nitrophenoxy or 2,4-dinitrophenyoxy, or polyhalophenoxy, such as pentachlorophenoxy
  • represent a symmetrical or preferably asymmetrical acid anhydride which is obtained, for example, by reacting a salt, for example an alkali
  • Activation and coupling reagents for activating carboxylic acids of the formula III in situ can be, in particular, carbodiimides, for example N, N'-di-C 1 -C 4 -alkyl- or N, N'-di-C 5 -C 7 -cycloalkyl- carbodiimide, such as diisopropylcarbodiimide or N, N'-dicyclohexylcarbodiimide, advantageously with the addition of an activation catalyst, such as N-hydroxysuccinimide or optionally substituted by halogen, C 1 -C 7 alkyl or C 1 -C 7 alkoxy, N- Hydroxy-benzotriazole or N-hydroxy-5-norbornene-2,3-dicarboxamide, C 1 -C 4 alkyl haloformate, for example isobutyl chloroformate, suitable carbonyl compounds, for example N, N-carbonyldiimidazole, suitable 1,2-oxa
  • Z 1 preferably denotes halogen, such as chlorine or bromine, and acyloxy, for example lower alkanoyloxy, such as acetyloxy.
  • the compounds of the formula IIIa in which Z 1 denotes halogen, such as chlorine are particularly suitable, which can be prepared, for example, by reacting the complementary alcohols, for example unsubstituted or substituted alkyl alcohols, aryl-lower alkyl alcohols or heterocyclyl-lower alkyl alcohols, in which the radicals as defined in the definition of unsubstituted or substituted alkoxycarbonyl, aryl-lower alkoxycarbonyl or heterocyclyl-lower alkoxycarbonyl R 5 , with phosgene or further analogues thereof, preferably, in particular, containing, instead of chlorine, halogen, other than bromine, containing, in particular, bromine, other than chlorine, halogen, in particular, which, in particular, contain bromine, other than bromine, halogen, other than chlorine,
  • the reaction of compounds of the formula II with corresponding compounds of the formula IIIa then also takes place under these conditions (cf. Staab, HA, Angew. Chemie 74 , 407 (1962)).
  • the reactions can be carried out under known reaction conditions, under normal conditions Temperatures, in or especially when using lower alkanoyl hydrides to activate the carboxylic acid of formula III, absence of inert Solvents or diluents are carried out, for example in acid amides, e.g. Carboxamides, such as dimethylformamide, dimethylacetamide or 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) pyrimidinone (DMPU), or amides of inorganic acids, such as Hexamethylphosphoric triamide, ethers e.g.
  • acid amides e.g. Carboxamides, such as dimethylformamide, dimethylacetamide or 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) pyrimidinone (DMPU)
  • amides of inorganic acids such as Hexamethylphosphoric triamide, ethers e.g.
  • cyclic ethers such as tetrahydrofuran or dioxane, or acyclic ethers, such as diethyl ether or ethylene glycol dimethyl ether, halogenated hydrocarbons such as halo lower alkanes e.g.
  • Sodium or potassium salts in the absence or presence of Catalysts, condensing agents or neutralizing agents, depending on the type of Reaction and / or the reactant under atmospheric pressure or in one closed vessel, under normal pressure or further under increased pressure, e.g. in which Pressure in the reaction mixture under the reaction conditions in a closed Tube is formed, and / or in an inert atmosphere, e.g. under an argon or Nitrogen atmosphere.
  • Preferred reaction conditions are those in the examples mentioned are analog.
  • the acylating agent e.g. a carboxylic acid halide or a carboxylic anhydride itself serve as a solvent.
  • the reaction process will expediently using customary analytical methods, in particular using thin-layer chromatography, tracked.
  • the reaction according to the invention is preferably carried out under mild conditions, in particular at temperatures between 0 ° C. and 60 ° C., for example at room temperature or slightly elevated temperatures up to about 45 ° C., for example at room temperature.
  • a compound of the formula R 1 -Z 1 in which Z 1 is halogen or with an activated derivative of a compound of the formula II, such as the corresponding chlorocarbonic acid ester, to prepare a compound of the formula I in which R 1 is aminocarbonyl or the rest of an N-substituted carbamic acid is advantageously carried out in the presence of an acid-binding agent, such as a non-acylatable base, in particular a tertiary nitrogen base, such as N-methylmorpholine, 4-dimethylaminopyridine, triethylamine or ethyldiisopropylamine.
  • the protective groups for functional groups in starting materials, their implementation should be avoided, especially carboxy, amino, hydroxy and / or mercapto groups, protection groups (conventional protecting groups), which are usually used in the synthesis of peptide compounds, but also of cephalosporins and penicillins and nucleic acid derivatives and sugars can be used.
  • These protective groups can already be present in the preliminary stages and are intended to relevant functional groups against unwanted side reactions such as acylations, Protect etherifications, esterifications, oxidations, solvolysis etc.
  • the protective groups can be selective, for example stereoselective Cause progress of implementations. Characteristic of protecting groups is that it is easy, d. H. can be split off without undesired side reactions, for example Solvolytic, reductive, photolytic or also enzymatic, e.g. B. also under physiological Conditions. Protective groups are only those residues that are in the End products are not available.
  • a carboxy group is e.g. B. protected as an ester group, the under gentle Conditions is selectively fissile.
  • a carboxy group protected in esterified form is esterified primarily by a lower alkyl group, which is preferably in the 1-position of the Lower alkyl group is branched or in the 1- or 2-position of the lower alkyl group suitable substituents is substituted.
  • a protected carboxy group which is esterified by a lower alkyl group is for example methoxycarbonyl or ethoxycarbonyl.
  • a protected carboxy group which is esterified by a lower alkyl group which in Branched position of the lower alkyl group is, for example, tert-lower alkoxycarbonyl, e.g. B. tert-butoxycarbonyl.
  • a protected carboxy group esterified by a lower alkyl group which in the 1- or 2-position of the lower alkyl group by suitable substituents is substituted, for example arylmethoxycarbonyl with one or two aryl radicals, wherein aryl is unsubstituted or z.
  • chlorine, and / or nitro means mono-, di- or tri-substituted phenyl, for example benzyloxycarbonyl, substituted by the substituents mentioned benzyloxycarbonyl, e.g. B. 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or Diphenylmethoxycarbonyl, z. B. Di (4-methoxyphenyl) methoxycarbonyl, further esterified by a lower alkyl group Carboxy, the lower alkyl group in the 1- or 2-position by suitable substituents is substituted, such as 1-lower alkoxy lower alkoxycarbonyl, e.g. B.
  • 2-tri-lower alkylsilyl-lower alkoxycarbonyl such as 2-tri-lower alkylsilylethoxycarbonyl, e.g. B. 2-trimethylsilylethoxycarbonyl or 2- (di-n-butyl-methyl-silyl) -ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as triphenylsilylethoxycarbonyl.
  • a carboxy group is also protected as an organic silyloxycarbonyl group.
  • An organic Silyloxycarbonyl group is, for example, a tri-lower alkylsilyloxycarbonyl group, e.g. B. Trimethylsilyloxycarbonyl.
  • the silicon atom of the silyloxycarbonyl group can also by two lower alkyl, e.g. B. methyl groups, and an amino or carboxy group a second molecule of formula I may be substituted.
  • Connections with such Protecting groups can e.g. B. with dimethylchlorosilane as a silylating agent.
  • a carboxy group is also in the form of an internal ester with a suitable one Distance, e.g. B. in the ⁇ position, to the carboxy group present in the molecule, d. H. protected in the form of a lactone, preferably a ⁇ -lactone.
  • a protected carboxy group is preferably tert-lower alkoxycarbonyl, e.g. B. tert-butoxycarbonyl, Benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl or diphenylmethoxycarbonyl.
  • a protected amino group is protected by an amino protecting group, e.g. B. in the form an acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alk-1-enylamino or silylamino group or as an azido group.
  • an amino protecting group e.g. B. in the form an acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alk-1-enylamino or silylamino group or as an azido group.
  • acyl is, for example, the acyl residue of an organic carboxylic acid with z. B. up to 18 carbon atoms, especially one optionally, e.g. Halogen or aryl, substituted lower alkane carboxylic acid or optionally, e.g. B. halogen, lower alkoxy or nitro, substituted benzoic acid, or preferably one Carbonic acid half ester.
  • acyl groups are preferably lower alkanoyl, such as formyl, Acetyl, propionyl or pivaloyl, halogen-lower alkanoyl, e.g. B.
  • 2-haloacetyl how 2-chloro, 2-bromo, 2-iodo, 2,2,2-trifluoro or 2,2,2-trichloroacetyl, optionally z.
  • tert-lower alkoxycarbonyl such as tert-butoxycarbonyl
  • Arylmethoxycarbonyl with one, two or three aryl radicals which, if necessary, for. B. by lower alkyl, especially tert-lower alkyl, such as tert-butyl, lower alkoxy, such as Methoxy, hydroxy, halogen, such as chlorine, and / or nitro mono- or poly-substituted Represent phenyl, e.g. B.
  • benzyloxycarbonyl 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl or di- (4-methoxyphenyl) methoxycarbonyl, Aroylmethoxycarbonyl, wherein the aroyl group is preferably optionally, e.g. B. benzoyl substituted by halogen such as bromine, e.g. B. phenacyloxycarbonyl, 2-halogeno-lower alkoxycarbonyl, e.g. B.
  • arylmethylamino group e.g. B. a mono-, di- or in particular triarylmethylamino group
  • the aryl radicals are in particular optionally substituted phenyl radicals.
  • Such groups are e.g. B. benzyl, diphenylmethyl or in particular tritylamino.
  • the mercapto group lies primarily as substituted arylthio or aryl-lower alkylthio, where aryl, for example, optionally e.g. B. by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and / or nitro substituted phenyl, e.g. B. 4-nitrophenylthio, in front.
  • acyl z. B the corresponding residue of a lower alkane carboxylic acid, an optionally z. B. by Lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and / or nitro-substituted benzoic acid, or in particular a carbonic acid semi-ester, like a carbonic acid lower alkyl half ester.
  • Corresponding protective groups are in primarily 1-lower alkanoyl-lower alk-1-en-2-yl, e.g. B.
  • 1-lower alkanoyl-prop-1-en-2-yl such as 1-acetyl-prop-1-en-2-yl, or lower alkoxycarbonyl-lower alk-1-en-2-yl, e.g. B. lower alkoxycarbonyl-prop-1-en-2-yl, such as 1-ethoxycarbonyl-prop-1-en-2-yl.
  • a silylamino group is, for example, a tri-lower alkylsilylamino group, e.g. B. Trimethylsilylamino or tert-butyldimethylsilylamino.
  • the silicon atom of the silylamino group can also only by two lower alkyl groups, e.g. B. methyl groups, and the Amino group or carboxyl group of a second molecule of the formula I can be substituted. Connections with such protective groups can be e.g. B. with the corresponding Produce chlorosilanes, such as dimethylchlorosilane, as the silylating agent.
  • an amino group can also be protected by conversion to the protonated form; the corresponding anions are primarily those of strong inorganic ones Acids such as sulfuric acid, phosphoric acid or hydrohalic acids, e.g. B. the chlorine or bromine anion, or of organic sulfonic acids, such as p-toluenesulfonic acid, in question.
  • Acids such as sulfuric acid, phosphoric acid or hydrohalic acids, e.g. B. the chlorine or bromine anion, or of organic sulfonic acids, such as p-toluenesulfonic acid, in question.
  • Preferred amino protecting groups are lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, Fluorenyl-lower alkoxycarbonyl, 2-lower alkanoyl-lower alk-1-en-2-yl or Lower alkoxycarbonyl-lower alk-1-en-2-yl, particularly preferably tert-butoxycarbonyl or Benzyloxycarbonyl.
  • a hydroxy group can be, for example, an acyl group, e.g. B. unsubstituted or lower alkanoyl substituted by halogen, such as chlorine, such as acetyl or 2,2-dichloroacetyl, or in particular by an acyl radical mentioned for protected amino groups be protected by a carbon dioxide semi-ester.
  • a preferred hydroxy protecting group is for example 2,2,2-trichloroethoxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or triphenylmethoxycarbonyl.
  • a hydroxy group can also by tri-lower alkylsilyl, e.g. B.
  • Two occurring in one molecule, in particular neighboring hydroxyl groups or an adjacent hydroxyl and amino group can, for example, by bivalent Protecting groups, such as one, preferably through one or two lower alkyl radicals or Oxo, substituted methylene group, be protected, e.g. B. by unsubstituted or substituted alkylidene, e.g. B. lower alkylidene, such as isopropylidene, cycloalkylidene, such as Cyclohexylidene, a carbonyl group or benzylidene.
  • bivalent Protecting groups such as one, preferably through one or two lower alkyl radicals or Oxo, substituted methylene group
  • alkylidene e.g. B. lower alkylidene, such as isopropylidene, cycloalkylidene, such as Cyclohexylidene, a carbonyl group or benzylidene.
  • a hydroxy group in the vicinity of a carboxy group can be replaced by Formation of an internal ester (lactone), in particular a ⁇ -lactone, to be protected.
  • lactone an internal ester
  • a protected hydroxy group by tri-lower alkylsilyl or as a lactone is preferred protected, especially by tert-butyl-dimethylsilyl.
  • Preferred Mercapto protecting groups are, for example, optionally in the phenyl radical, for. B. by Methoxy or nitro, substituted benzyl, such as 4-methoxybenzyl, optionally in the phenyl radical, e.g. B.
  • acylaminomethyl such as acetamidomethyl, iso-butyrylacetamidomethyl or 2-chloroacetamidomethyl
  • benzoyl, benzyloxycarbonyl or alkyl in particular Lower alkylaminocarbonyl, such as ethylaminocarbonyl, and lower alkylthio, such as S-ethylthio or S-tert-butylthio, or S-sulfo.
  • the splitting off of the protective groups that are not part of the desired end product of formula I are, e.g. B. the carboxy, amino, hydroxy and / or mercapto protecting groups, takes place in a manner known per se, e.g. B. by means of solvolysis, in particular hydrolysis, Alcoholysis or acidolysis, or by means of reduction, in particular hydrogenolysis or by means of other reducing agents, as well as photolysis, optionally stepwise or at the same time, whereby enzymatic methods can also be used.
  • the protecting groups are, for example, in the section above about "Protective groups" standard works described.
  • protected carboxy e.g. B. tert-lower alkoxycarbonyl, in 2 position by a trisubstituted silyl group or in the 1-position by lower alkoxy or Niederalkylthio substituted Niederalkoxycarbonyl or optionally substituted Diphenylmethoxycarbonyl by treatment with a suitable acid, such as formic acid, Hydrogen chloride or trifluoroacetic acid, optionally with the addition of a nucleophile Compound, such as phenol or anisole, can be converted into free carboxy.
  • a suitable acid such as formic acid, Hydrogen chloride or trifluoroacetic acid
  • a nucleophile Compound such as phenol or anisole
  • Suitable substitutes may also be used Benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl, also by reduction, e.g. B. by Treat with an alkali metal, such as sodium dithionite, or with a reducing Metal, e.g. B. zinc, or a reducing metal salt, such as a chromium II salt, e.g. B. Chromium II chloride, usually in the presence of a hydrogen donor By means of that together with the metal can generate nascent hydrogen, such as an acid, in primarily a suitable carboxylic acid, such as an optionally, e.g. B.
  • hydroxy, substituted lower alkane carboxylic acid e.g. B. acetic acid, formic acid, glycolic acid, diphenylglycolic acid, Lactic acid, mandelic acid, 4-chloromandelic acid or tartaric acid, or an alcohol or thiol, preferably adding water, into free carboxy be transferred.
  • a reducing metal or metal salt such as described above, 2-halo lower alkoxycarbonyl (optionally after conversion a 2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl can be converted into free carboxy.
  • Aroylmethoxycarbonyl can also be treated by treatment with a nucleophile, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide, cleaved will.
  • a nucleophile preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide
  • 2- (trisubstituted silyl) lower alkoxycarbonyl such as 2-tri-lower alkylsilyl lower alkoxycarbonyl, can also be done by treating with a salt providing the fluoride anion hydrofluoric acid, such as an alkali metal fluoride, e.g. B.
  • sodium or Potassium fluoride optionally in the presence of a macrocyclic polyether ("crown ether"), or with a fluoride of an organic quaternary base, such as tetraniederalkylammonium fluoride or tri-lower alkylaryl-lower alkyl ammonium fluoride, e.g. B. tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic, polar Solvents such as dimethyl sulfoxide or N, N-dimethylacetamide in free Carboxy be transferred.
  • a macrocyclic polyether such as tetraniederalkylammonium fluoride or tri-lower alkylaryl-lower alkyl ammonium fluoride, e.g. B. tetraethylammonium fluoride or tetrabutylammonium fluoride
  • organic silyloxycarbonyl such as tri-lower alkylsilyloxycarbonyl, e.g. B. Trimethylsilyloxycarbonyl
  • protected carboxy can in the usual way solvolytic, e.g. B. by treatment with water, an alcohol or acid, or in addition Fluoride, as described above, are released.
  • Esterified carboxy can also are released enzymatically, for example by esterases or suitable peptidases, e.g. B. esterified arginine or lysine, such as lysine methyl ester, using trypsin.
  • an inner Esters such as ⁇ -lactone
  • protected carboxy can be hydrolysed in the presence a hydroxide-containing base, such as an alkaline earth metal hydroxide or in particular an alkali metal hydroxide, e.g. B. NaOH, KOH or LiOH, especially LiOH, are released, wherein at the same time the correspondingly protected hydroxy group is released.
  • a hydroxide-containing base such as an alkaline earth metal hydroxide or in particular an alkali metal hydroxide, e.g. B. NaOH, KOH or LiOH, especially LiOH
  • a protected amino group is used in a manner known per se and depending on the nature of the protective groups in various ways, preferably by means of solvolysis or reduction, free.
  • Lower alkoxycarbonylamino such as tert-butoxycarbonylamino, can be in the presence of Acids, for example mineral acids, e.g. B.
  • hydrogen halide such as hydrogen chloride or hydrogen bromide, in particular hydrogen bromide, or of sulfur or or Phosphoric acid, preferably hydrogen chloride
  • polar solvents such as Water or a carboxylic acid, such as acetic acid, or ethers, preferably cyclic ethers, such as dioxane, 2-halogeno lower alkoxycarbonylamino (optionally after conversion a 2-bromo-lower alkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonylamino group), Aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can e.g. B.
  • Aroylmethoxycarbonylamino can also by treatment with a nucleophilic, preferably salt-forming Reagent such as sodium thiophenolate and 4-nitrobenzyloxycarbonylamino as well by treatment with an alkali metal, e.g. B. sodium dithionite, cleaved.
  • a suitable reducing agent such as zinc
  • carboxylic acid such as aqueous acetic acid.
  • Aroylmethoxycarbonylamino can also by treatment with a nucleophilic, preferably salt-forming Reagent such as sodium thiophenolate and 4-nitrobenzyloxycarbonylamino as well by treatment with an alkali metal, e.g. B. sodium dithionite, cleaved.
  • Optionally substituted diphenylmethoxycarbonylamino, tert-lower alkoxycarbonylamino or 2- (trisubstituted silyl) lower alkoxycarbonylamino, such as 2-tri-lower alkylsilyl lower alkoxycarbonylamino, can be treated with a suitable acid, e.g. B. formic or trifluoroacetic acid, optionally substituted benzyloxycarbonylamino e.g.
  • a suitable hydrogenation catalyst such as a palladium catalyst, preferably in polar ones Solvents such as di-lower alkyl alkanoylamides, e.g. B.
  • Ethers such as cyclic ethers e.g. B. dioxane, or alcohols, such as methanol, ethanol or Propanol, with methanol being particularly preferred, optionally substituted triarylmethylamino or formylamino z. B. by treatment with an acid, such as mineral acid, e.g. As hydrochloric acid, or an organic acid, e.g. B. ants, vinegar or Trifluoroacetic acid, optionally in the presence of water, and one protected as silylamino Amino group e.g. B. be released by hydrolysis or alcoholysis.
  • an acid such as mineral acid, e.g. As hydrochloric acid, or an organic acid, e.g. B. ants, vinegar or Trifluoroacetic acid, optionally in the presence of water, and one protected as silylamino Amino group e.g. B. be released by hydrolysis or alcoholysis.
  • 2-chloroacetyl, protected amino group can be treated with thiourea in the presence of a base, or with a thiolate salt such as one Alkali metal thiolate of thiourea, and subsequent solvolysis, such as alcoholysis or hydrolysis, the resulting substitution product are released.
  • a thiolate salt such as one Alkali metal thiolate of thiourea
  • solvolysis such as alcoholysis or hydrolysis
  • Protected amino group can also be treated with a fluoride anion providing the salt of hydrofluoric acid as above in connection with the release a correspondingly protected carboxy group specified in the free amino group be transferred.
  • You can also bond directly to a heteroatom, such as nitrogen Cleave silyl, such as trimethylsilyl, using fluoride
  • Protected amino in the form of an azido group is e.g. B. by reduction into free Amino converted, for example by catalytic hydrogenation with hydrogen in the presence a hydrogenation catalyst such as platinum oxide, palladium or Raney nickel Reduction using mercapto compounds, such as dithiothreitol or mercaptoethanol, or also by treatment with zinc in the presence of an acid such as acetic acid.
  • the catalytic Hydrogenation is preferably carried out in an inert solvent such as a halogenated one Hydrocarbon, e.g. B. methylene chloride, or in water or a mixture of water and an organic solvent, such as an alcohol or dioxane, at about 20 ° C to 25 ° C, or with cooling or heating.
  • One by a suitable acyl group, a tri-lower alkylsilyl group or by optionally substituted 1-phenyl-lower alkyl protected hydroxy or mercapto group is released analogously to an appropriately protected amino group.
  • One by 2,2-dichloroacetyl Protected hydroxy or mercapto group is, for. B. by basic hydrolysis, one by tert-lower alkyl or by a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical protected hydroxy or mercapto group by acidolysis, e.g. B. by treatment with a mineral acid or a strong carboxylic acid, e.g. B. trifluoroacetic acid released.
  • Protected by pyridyldiphenylmethyl Mercapto can e.g. B. by mercury II salts at pH 2-6 or by zinc / acetic acid or electrolytic reduction, by acetamidomethyl or iso-butyrylamidomethyl protected mercapto e.g. B. by reaction with mercury II salts at pH 2-6, by 2-chloroacetamidomethyl protected mercapto e.g. B. by 1-piperidinothiocarboxamide, S-ethylthio, S-tert-butylthio and S-sulfo e.g. B.
  • a bivalent protective group preferably e.g. B. one by lower alkyl or doubly substituted methylene group, such as by lower alkylidene, e.g. B. isopropylidene, Cycloyalkylidene, e.g. B. cyclohexylidene, or benzylidene
  • a tri-lower alkylsilyl group is also used by acidolysis, e.g. B. by mineral acid, preferably hydrofluoric acid, or a split off strong carboxylic acid.
  • 2-halogeno lower alkoxycarbonyl is represented by the above mentioned reducing agents, for. B. reducing metal, such as zinc, reducing metal salts, such as chromium II salts, or by sulfur compounds, for example sodium dithionite or preferably sodium sulfide and carbon disulfide.
  • Esterified Hydroxy groups e.g. B. lower alkanoyloxy, such as acetyloxy, can also by esterases are released, acylated amino for example by suitable peptidases.
  • the temperatures for the release of the protected functional groups are preferably from -80 to 100 ° C, particularly preferably -20 to 50 ° C, for example between 10 and 35 0 C, such as in the range of room temperature.
  • the protecting groups are chosen so that at the same time more than one Group can be split off, for example acidolytically, such as by treatment with Trifluoroacetic acid, or with hydrogen and a hydrogenation catalyst such as one Palladium-carbon catalyst.
  • the groups can also be selected that they are not all split off at the same time, but in the desired order can, the corresponding intermediates being obtained.
  • the starting compound of formula II is obtainable from 2- [3 (S) -amino-2 (R) -hydroxy-4-phenylbutyl] -N-tert-butyl-decahydro- (4aS, 8aS) -isoquinolin-3 (S) carboxamide (can be prepared analogously to EP 0 432 695, Example 33) which can also be obtained, for example, by reacting a compound of the formula VIII, wherein P 1 is an amino protecting group, as defined above under process a), in particular tert-butoxycarbonyl or benzyloxycarbonyl, which can be prepared according to Evans et al., J. Org. Chem.
  • N tert-butyldecahydro- (4aS, 8aS) -isoquinoline-3 (S) carboxamide produced according to EP 0 432 694
  • a polar solvent such as an alcohol, e.g. As methanol or ethanol, at an elevated temperature, e.g. B.
  • a compound of formula IX in which P 1 has the last-mentioned meanings, and subsequent cleavage of the amino protecting group P 1 can be obtained, for example in the case of tert-butoxycarbonyl P 1, by cleavage with an acid, such as a mineral acid, for example a hydrohalic acid, such as hydrochloric acid, or in the presence of a strong organic acid, such as formic acid, in organic solvents, for example an ether, for example a cyclic ether, such as dioxane, or in the case of a liquid organic acid, such as formic acid, without solvent; or in the case of benzyloxycarbonyl by hydrogenation in the presence of a catalyst, for example a noble metal catalyst, for example bound to a support such as carbon, silica gel or aluminum oxide, preferably Pd on activated carbon, at atmospheric pressure or elevated pressure, preferably at atmospheric pressure, in a polar solvent, for example an alcohol,
  • an acid such as a mineral acid, for example
  • the compound of the formula II can also be published in EP 0 432 695 ( on June 19, 1991) can be obtained.
  • the starting compounds of formula III are commercially available, known or after known methods can be produced.
  • heterocyclylmethyl in which heterocyclyl is connected via a ring nitrogen atom, substituted aryl-lower alkanoyl, which preferably by reacting one with halomethyl, such as chloromethyl or bromomethyl, substituted aryl-lower alkanoyl radical, such as chloromethylbenzoyl or bromomethylbenzoyl, with a corresponding heterocyclic nitrogen base, such as piperidine, Piperazin, 1-Niederalkylpiperazin, 1-Niederalkanyolpiperazin or in particular morpholine or thiomorpholine, with nucleophilic substitution of the halogen atom.
  • halomethyl such as chloromethyl or bromomethyl
  • substituted aryl-lower alkanoyl radical such as chloromethylbenzoyl or bromomethylbenzoyl
  • a corresponding heterocyclic nitrogen base such as piperidine, Piperazin, 1-Niederalkylpiperazin, 1-Niederal
  • amino acid derivatives of the formula III in which the ⁇ -amino group alkylated by a residue selected from phenyl-lower alkyl or heterocyclyl-lower alkyl is, for example, possible by reductive amination of the (if necessary other groups, which should not participate in the reaction, protected) amino acid, which has a primary or secondary ⁇ -amino group with a phenyl-lower alkyl ketone or aldehyde, such as benzaldehyde, or heterocyclyl-lower alkyl ketone, or aldehyde, for example heterocyclyl aldehyde, e.g.
  • Furan aldehyde such as furan-2-aldehyde, or pyridine aldehyde, such as pyridin-3-aldehyde, or imidazolylaldehyde, such as imidazol-4-ylaldehyde (N-protected if necessary, e.g. by trityl, which in the connection as described above of the formula III or the protected end product of the formula I are split off can, as described above) for example under catalytic hydrogenation, e.g. in Presence of a heavy metal catalyst such as Raney nickel at normal pressure or Pressure from 1 to 100 bar, preferably at about 100 bar, or with reduction by means of complex borohydrides such as sodium cyanoborohydride.
  • a heavy metal catalyst such as Raney nickel at normal pressure or Pressure from 1 to 100 bar, preferably at about 100 bar, or with reduction by means of complex borohydrides such as sodium cyanoborohydride.
  • the isocyanates of the formula IIIb can be obtained, for example, from the corresponding amine precursors by converting the amino group to the isocyanato group, e.g. by reaction with phosgene in the heat, e.g. at reflux conditions, or by Dropwise of the liquid, primary or secondary or dissolved in a solvent tertiary amine to an excess of phosgene in a suitable solvent (Toluene, xylene, ligroin, chlorobenzene, ⁇ -chloronaphthalene etc.) with cooling (for example to - 50 to 0 ° C), with a mixture of carbamoyl chloride and Amine hydrochloride forms, which then at elevated temperature (for example at 50 ° C to Reflux temperature) until phosgenation is complete, with HCl elimination.
  • a suitable solvent for example to - 50 to 0 ° C
  • the carboxylic acid of formula V is either present with a free carboxy group or as a reactive one Derivative thereof, for example as derived from the free carboxy compound activated ester, as a reactive anhydride, or further as a reactive cyclic amide.
  • the reactive derivatives can also be formed in situ.
  • Activated esters of the compound of formula V with a carboxy group are particular unsaturated esters on the linking carbon atom of the esterifying radical, e.g. of the vinyl ester type, such as vinyl ester (obtainable, for example, by transesterification of a corresponding Vinyl acetate esters; Activated vinyl ester method), carbamoyl ester (obtainable, for example, by treating the corresponding acid with an isoxazolium reagent; 1,2-oxazolium or Woodward method), or 1-lower alkoxy vinyl ester (available e.g. B.
  • vinyl ester type such as vinyl ester (obtainable, for example, by transesterification of a corresponding Vinyl acetate esters; Activated vinyl ester method), carbamoyl ester (obtainable, for example, by treating the corresponding acid with an isoxazolium reagent; 1,2-oxazolium or Woodward method), or 1-lower alkoxy vinyl ester (available e.g. B.
  • N, N'-disubstituted Amidino esters obtained e.g. by treating the corresponding acid with a suitable one N, N'-disubstituted carbodiimide, e.g. B. N, N'-dicyclohexylcarbodiimide; Carbodiimide method), or N, N-disubstituted amidino esters (obtainable e.g.
  • Inner esters, e.g. B. ⁇ -lactones can be used.
  • Anhydrides of the acid can be symmetrical or, preferably, mixed anhydrides of these Be acid, e.g. B. anhydrides with inorganic acids, such as acid halides, in particular Acid chlorides (obtainable e.g. by treating the corresponding acid with thipnyl chloride, Phosphorus pentachloride or oxalyl chloride; Acid chloride method), azides (available e.g. B. from a corresponding acid ester via the corresponding hydrazide and its treatment with nitrous acid; Azide method), anhydrides with carbonic acid half-esters, e.g. B.
  • inorganic acids such as acid halides, in particular Acid chlorides (obtainable e.g. by treating the corresponding acid with thipnyl chloride, Phosphorus pentachloride or oxalyl chloride; Acid chloride method), azides (available e.g. B. from a corresponding acid ester via the corresponding hydrazide and
  • carbonic acid lower alkyl half-esters obtainable, for example, by treating the corresponding Acid with lower alkyl chloroformates or with a 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline; Mixed O-alkyl carbonic anhydride method
  • anhydrides with dihalogenated, especially dichlorinated, phosphoric acid obtainable e.g. by treating the corresponding acid with phosphorus oxychloride; Phosphorus oxychloride method
  • anhydrides with other phosphoric acid derivatives e.g.
  • phenylacetic acid Pivalic acid or trifluoroacetic acid chloride; Mixed carboxylic anhydride method) or with organic sulfonic acids (obtainable e.g. by treating a salt, such as an alkali metal salt, the corresponding acid with a suitable organic Sulfonic acid halide, such as lower alkane or aryl, e.g. B. methane or p-toluenesulfonic acid chloride; Mixed sulfonic anhydride method) and symmetrical anhydrides (obtainable e.g. by condensation of the corresponding acid in the presence of a Carbodiimides or 1-diethylaminopropine; Method of symmetrical anhydrides).
  • organic sulfonic acids obtainable e.g. by treating a salt, such as an alkali metal salt, the corresponding acid with a suitable organic Sulfonic acid halide, such as lower alkane or aryl, e.g. B. methane or p-
  • Suitable cyclic amides are in particular amides with five-membered diazacycles aromatic character, such as amides with imidazoles, e.g. B. Imidazole (available e.g. through Treating the corresponding acid with N, N'-carbonyldiimidazole; Imidazole method), or pyrazole, e.g. B. 3,5-dimethylpyrazole (obtainable, for example, via the acid hydrazide Treatment with acetylacetone; Pyrazolide method).
  • amides with imidazoles e.g. B. Imidazole (available e.g. through Treating the corresponding acid with N, N'-carbonyldiimidazole; Imidazole method), or pyrazole, e.g. B. 3,5-dimethylpyrazole (obtainable, for example, via the acid hydrazide Treatment with acetylacetone; Pyrazolide method).
  • derivatives of a carboxylic acid used as an acylating agent are also formed in situ. So you can z. B. N, N'-disubstituted Amidino esters form in situ by mixing the starting material of formula IV and the acid of formula V used as the acylating agent in the presence of a suitable N, N'-disubstituted carbodiimide, e.g. B. N, N'-cyclohexylcarbodiimide, for reaction brings, for example in the presence of a suitable base such as triethylamine.
  • a suitable N, N'-disubstituted carbodiimide e.g. B. N, N'-cyclohexylcarbodiimide
  • an N, N'-disubstituted Carbodiimides e.g. B. N, N'-dicyclohexylcarbodiimide
  • an N-hydroxyamine or N-hydroxy amides e.g. B. N-hydroxysuccinimide
  • a suitable base e.g. B. 4-dimethylamino-pyridine.
  • N, N, N ', N'-tetraalkyluronium compounds such as O-benzotriazol-1-yl-N, N, N', N'-tetra-methyl-uronium hexafluorophosphate, Achieve activation in situ.
  • phosphoric anhydrides of the carboxylic acids of the formula V can be used in situ be prepared by using an alkylphosphoric amide such as hexamethylphosphoric triamide in the presence of a sulfonic anhydride, such as 4-toluenesulfonic anhydride, with a salt such as a tetrafluoroborate, e.g. B.
  • hexamethylphosphoric triamide such as benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluoride, preferably in the presence a racemization-reducing additive, such as N-hydroxybenztriazole.
  • the amino group of compounds of formula IV that participates in the reaction carries preferably at least one reactive hydrogen atom, especially if the thus reacting carboxy group is in a reactive form; the connection of the Formula IV can also itself be present as a reactive derivative, i.e. with the Amino group in reactive form, e.g. B. by reaction with a phosphite, such as Diethyl chlorophosphite, 1,2-phenylene chlorophosphite, ethyl dichlorophosphite, ethylene chlorophosphite or tetraethyl pyrophosphite.
  • a derivative of such a compound with a Amino group is e.g. B. also a carbamic acid halide, which is in the reaction participating amino group by halocarbonyl, e.g. B. chlorocarbonyl, is substituted.
  • the condensation to produce an amide bond can be carried out in a manner known per se be carried out, for example as in standard works such as "Houben-Weyl, Methods der organic chemistry ", 4th edition, volume 15 / II (1974), volume IX (1955) volume E 11 (1985), Georg Thieme Verlag, Stuttgart, "The Peptides” (E. Gross and J. Meienhofer, Ed.), Vol. 1 and 2, Academic Press, London and New York, 1979/1980, or M. Bodansky, "Principles of Peptide Synthesis", Springer-Verlag, Berlin 1984.
  • the condensation of a free carboxylic acid with the corresponding amine can preferably be carried out in the presence of one of the usual condensing agents.
  • Usual Condensing agents are e.g. B. carbodiimides, for example diethyl, dipropyl, N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide or in particular dicyclohexylcarbodiimide, also suitable carbonyl compounds, for example carbonylimidazole, 1,2-oxazolium compounds, e.g. B.
  • diphenylphosphoryl azide diethylphosphoryl cyanide
  • Phenyl-N-phenylphosphoroamidochloridate bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride or 1-benzotriazolyloxy tris (dimethylamino) phosphonium hexafluorophosphate.
  • an organic base is added, e.g. B. a tri-lower alkylamine voluminous residues, e.g. B. ethyldiisopropylamine, and / or a heterocyclic base, e.g. B. Pyridine, 4-dimethylaminopyridine or preferably N-methylmorpholine.
  • the condensation of activated esters, reactive anhydrides or reactive cyclic Amides with the corresponding amines are usually in the presence of an organic Base, e.g. B. simple tri-lower alkylamines, e.g. B. triethylamine or tributylamine, or one of the above-mentioned organic bases. If desired a condensing agent is also used, as for free Carboxylic acids is described.
  • the condensation of acid anhydrides with amines can e.g. B. in the presence of inorganic Carbonates, e.g. B. ammonium or alkali metal carbonates or bicarbonates, such as sodium or potassium carbonate or bicarbonate (usually together with a sulfate), the reaction of sulfonic acid halides, such as Sulfonic acid chlorides, in the presence of hydroxides, e.g. B. alkali metal hydroxides, such as Sodium hydroxide or potassium hydroxide.
  • inorganic Carbonates e.g. B. ammonium or alkali metal carbonates or bicarbonates, such as sodium or potassium carbonate or bicarbonate (usually together with a sulfate)
  • sulfonic acid halides such as Sulfonic acid chlorides
  • hydroxides e.g. B. alkali metal hydroxides, such as Sodium hydroxide or potassium hydroxide.
  • Carboxylic acid halides for example the chlorocarbonic acid derivative derived from the acid of the formula V, are preferably in the presence with the corresponding amines an organic amine, e.g. B. the aforementioned tri-lower alkyl amines or heterocyclic Bases, optionally in the presence of a hydrogen sulfate, condensed.
  • the condensation is preferably carried out in an inert, aprotic, preferably anhydrous, Solvent or solvent mixture carried out, for example in one Carboxamide, e.g. B. formamide or dimethylformamide, a halogenated hydrocarbon, e.g. B. methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, e.g. B. acetone, a cyclic ether, e.g. B. tetrahydrofuran, an ester, e.g. B. ethyl acetate, or a nitrile, e.g. B.
  • Carboxamide e.g. B. formamide or dimethylformamide
  • a halogenated hydrocarbon e.g. B. methylene chloride, carbon tetrachloride or chlorobenzene
  • a ketone e.g. B. acetone
  • a cyclic ether e.g
  • acetonitrile or in a mixture thereof, optionally at reduced or elevated temperature, e.g. B. in a temperature range from about -40 ° C to about +100 ° C, preferably from about -10 ° C to about +50 ° C, and without inert gas or under inert gas, e.g. B. nitrogen or argon atmosphere.
  • reduced or elevated temperature e.g. B. in a temperature range from about -40 ° C to about +100 ° C, preferably from about -10 ° C to about +50 ° C
  • inert gas or under inert gas e.g. B. nitrogen or argon atmosphere.
  • aqueous for example alcoholic, e.g. As ethanol, or aromatic solvents or solvent mixtures, e.g. As benzene or toluene, are possible.
  • acetone can optionally also be added.
  • the condensation can also be carried out according to the technique known as solid-phase synthesis, which goes back to R. Merrifield and for example in Angew. Chem. 97, 801 - 812 (1985), Naturwissenschaften 71, 252-258 (1984) or in R. A. Houghten, Proc. Natl. Acad. Sci. USA 82, 5131-5135 (1985).
  • a starting compound of the formula IV is preferably prepared from a compound of the formula VI which can be prepared as described under process c) by either using L-asparagine which is N-protected by an amino protecting group P 2 , for example ⁇ - (N-benzyloxycarbonyl -) - L-asparagine, or a reactive acid derivative thereof, in particular the p-nitrophenyl ester, preferably amidated in the presence of a tertiary nitrogen base, such as triethylamine or N-ethyldiisopropylamine, as described above, especially in an acid amide, for example dimethylformamide, at temperatures between 0 and 50 ° C., preferably at room temperature, to give the compound of the formula IV which is protected by P 2 N and which is eliminated by splitting off the protective group P 2 under the conditions mentioned for the splitting off of the protective group from a compound of the formula IX into the compound of the formula IV is converted.
  • L-asparagine which is N-
  • starting materials of formula VI and / or VII are functional groups that are not should participate in the reaction, if necessary protected by protective groups.
  • the Protecting groups and their introduction are as described above under method a).
  • This reaction may be hindered by acyl migration of the R 1 radical to the free amino group in the compound of the formula VI.
  • the process variant is therefore preferably limited to those starting materials and reaction conditions which allow a reaction without disruptive acyl migration.
  • a starting compound of the formula VI is preferably prepared by reacting a compound of the formula IX defined above with a carboxylic acid of the formula III, which has also already been defined, or a reactive derivative thereof, under reaction conditions analogous to those described for process a), one obtained by P 1 receives protected derivative of a compound of formula VI, from which the protective group, for example tert-butoxycarbonyl or benzyloxycarbonyl, preferably as described in the deprotection from a compound of formula IX, is split off to obtain the compound of formula VI.
  • the protective group for example tert-butoxycarbonyl or benzyloxycarbonyl, preferably as described in the deprotection from a compound of formula IX
  • a starting compound of the formula VII is obtained, for example, by amidating a carboxy-protected derivative of L-asparagine, for example protected with one of the carboxy protective groups protected under process a), with quinoline-2-carboxylic acid under the amidation conditions mentioned above, preferably the conditions for Preparation of compounds of the formula II from a compound of the formula X have been mentioned after the protective group P 2 has been split off, and the carboxy protective group has been split off, giving the compound of the formula VII.
  • Process variant c) is preferably not used, but instead one of processes a) or b) used to obtain compounds of the formula I.
  • cyclic ethers such as tetrahydrofuran or dioxane, or acyclic ethers, such as diethyl ether or ethylene glycol dimethyl ether, halogenated hydrocarbons, such as Halo lower alkanes, e.g.
  • Methylene chloride or chloroform ketones, such as acetone, nitriles, such as acetonitrile, acid anhydrides such as acetic anhydride, esters such as ethyl acetate, Bisalkane sulfines such as dimethyl sulfoxide, nitrogen heterocycles such as pyridine, or mixtures these solvents, especially in anhydrous solvents or solvent mixtures, the most suitable solvents for the above Reactions can be selected using where appropriate and appropriate of salts of the compounds used, in particular of metal salts used Cabonic acids such as the alkali or alkaline earth metal salts, e.g.
  • Salts of compounds of the formula I can be prepared in a manner known per se will. So you can salts of compounds of formula I with acidic groups such. B. by treatment with metal compounds such as alkali metal salts of suitable ones organic carboxylic acids, e.g. B. the sodium salt of 2-ethyl-hexanoic acid, with organic Alkali or alkaline earth metal compounds, such as the corresponding hydroxides, Carbonates or bicarbonates, such as sodium and potassium hydroxide, carbonate or -hydrogen carbonate, with appropriate calcium compounds or with ammonia or form a suitable organic amine, preferably stoichiometric Amounts or only a small excess of the salt-forming agent used.
  • metal compounds such as alkali metal salts of suitable ones organic carboxylic acids, e.g. B. the sodium salt of 2-ethyl-hexanoic acid, with organic Alkali or alkaline earth metal compounds, such as the corresponding hydroxides, Carbonates or bicarbonates, such as sodium and
  • the preferred acid addition salts of compounds of formula I are obtained in the usual way Way, e.g. by treatment with an acid, e.g. an organic acid or one inorganic acid, or with a suitable ion exchanger.
  • Inner salts of Compounds of the formula I which contain acidic and basic salt-forming groups, e.g. a free carboxy group and a free amino group, for example, by Neutralize salts, such as acid addition salts, to the isoelectric point, e.g. B. with weak bases, or by treatment with ion exchangers.
  • Salts can be converted into the free compounds in the usual way, metal and Ammonium salts, for example by treatment with suitable acids or acids Ion exchangers, and acid addition salts, for example by treatment with a suitable basic agents or basic ion exchangers.
  • the conversion of a salt of a compound of formula I into another salt takes place for example by converting a salt into the free compound, as last described, and subsequent conversion of the free compound into another salt, as last described, or directly by converting one salt into another, for example by salting by means of chromatography, e.g. by means of gel permeation chromatography, or from a solution with an excess of that to form the new one Salt needed counter ion.
  • Mixtures of stereoisomers, ie mixtures of diastereomers and / or enantiomers, such as for example racemic mixtures, can be prepared in a manner known per se by suitable means Separation processes are separated into the corresponding isomers. So mixtures of diastereomers by fractional crystallization, chromatography, solvent distribution etc. are separated into the individual diastereomers. Racemate can after Conversion of the optical antipodes into diastereomers, for example by conversion with optically active connections, e.g. B. optically active acids or bases, by chromatography on column materials covered with optically active compounds or through enzymatic methods, e.g. B. by selective reaction of only one of the two enantiomers, be separated from each other. This separation can take place at the level of either Starting products as well as the compounds of formula I themselves take place.
  • an amino or carboxamide group substitute a carboxy group present in free or in reactive form esterify or amidate or an esterified or amidated carboxy group convert into a free carboxy group.
  • Suitable agents for the alkylation of a carboxamide group in a compound of the formula I are, for example, diazo compounds, e.g. B. diazomethane. You can use diazomethane decompose in an inert solvent, the free methylene formed with the Carboxamide group in the compound of formula I reacts.
  • the decomposition of diazomethane is preferably carried out catalytically, for. B. in the presence of a noble metal in fine distributed form, e.g. B. copper, or a precious metal salt, e.g. B. copper (I) chloride or Copper (II) sulfate.
  • Alkylating agents are also mentioned in German Offenlegungsschrift 2,331,133, e.g. B. Alkyl halides, sulfonic acid esters, sea wine salts or 1-substituted 3-aryltriazenes, which one under the reaction conditions mentioned there with a compound of Formula I can implement with a carboxamide group.
  • Further alkylating agents are selected from corresponding unsubstituted or substituted lower alkyl compounds which are used to introduce substituted or unsubstituted lower alkyl radicals mentioned above for the radical R 1 of an N-substituted carbamic acid which carry an additional substituent X, where X is a leaving group.
  • a leaving group is in particular a nucleofugic leaving group selected from hydroxy esterified with a strong inorganic or organic acid, such as with a mineral acid, e.g. B. hydrohalic acid, such as hydrochloric acid, hydrobromic acid or hydroiodic acid, or with a strong organic sulfonic acid, such as an optionally, for. B.
  • halogen such as fluorine, substituted lower alkanesulfonic acid or an aromatic sulfonic acid
  • B an optionally substituted by lower alkyl, such as methyl, halogen, such as bromine, and / or nitro, benzenesulfonic acid, for.
  • B a methanesulfonic, trimethanesulfonic or p-toluenesulfonic acid, esterified hydroxy or hydroxy esterified with hydrochloric acid.
  • the substitution reaction is optionally at a reduced or elevated temperature, for. B. in a temperature range from about -40 ° to about 100 ° C, preferably from about -10 ° to about 50 ° C, and optionally under inert gas, e.g. B. nitrogen or argon atmosphere.
  • esterification or amidation of a carboxy group in a compound of the formula I for example to amidate a free carboxy group of an amino acid such as Glu or Asp, with ammonia, lower alkylamine or di-lower alkylamine, can, if desired, use the free acid or the free acid in any of the above convert reactive derivatives and with an alcohol, ammonia, a primary or implement a secondary amine, or you can esterify the free acid or a reactive salt, e.g. B. the cesium salt, with a reactive derivative implement an alcohol.
  • the cesium salt of a carboxylic acid implement a halide or sulfonic acid ester corresponding to the alcohol.
  • the Esterification of the carboxy group can also be carried out with other conventional alkylating agents take place, e.g. B. with diazomethane, alkyl halides, sulfonic acid esters, sea wine salts or 1-substituted 3-aryltriazenes, etc.
  • an existing free amino group can be acylated, for example to introduce one of the radicals mentioned for R 1 apart from hydrogen.
  • the acylation is carried out according to the method under a) above or one of the methods mentioned for protecting groups or, for example, according to one of the methods mentioned in Organikum, 17th edition, VEB Deutscher Verlag dermaschineen, Berlin (Ost) 1988.
  • the ⁇ -amino group can be alkylated by a radical selected from lower alkyl, phenyl-lower alkyl or heterocyclyl-lower alkyl, for example by reductive amination of the amino group the amino acid residue (protected, if necessary, in other groups which should not take part in the reaction) with a lower alkyl aldehyde or ketone, a phenyl lower alkyl aldehyde or ketone or a heterocyclyl lower alkyl aldehyde or ketone, for example formaldehyde, heterocyclyl aldehyde, for example furan aldehyde, such as furan-2 aldehyde, pyridine aldehyde, such as pyridine-3-aldehyde, or imidazolylaldehyde, such as imidazol-4-
  • halogen atom if it is in particular chlorine or bromine, can, if necessary, by Finkelstein reaction in a polar aprotic solvent, in particular a ketone, such as acetone , are converted with sodium iodide into the corresponding compound of formula I with 2-iodo-lower alkanoyl, in particular 2-iodoacetyl.
  • 2-Halo-lower alkanoyl in particular 2-iodoacetyl, can then be reacted with an amino, lower alkylamino or di-lower alkylamino-lower alkanol or an amino, lower alkylamino or di-lower alkylamino-lower alkoxy lower alkanol, preferably in the presence of bases such as carbonates or hydrogen carbonates, for example alkali metal carbonates or -hydrogen carbonates, such as sodium or potassium carbonate or sodium or potassium hydrogen carbonate, in the latter solvents, or further (in particular if it is 2-chloro or 2-bromo-lower alkanoyl), also the corresponding (if necessary, N-protected) alkali metal alcoholates Amino, lower alkylamino or di-lower alkylamino lower alkanols or amino, lower alkylamino or di-lower alkylamino lower alkoxy lower alkanols, which can be prepared, for example, from
  • R 1 is amino, lower alkylamino or di-lower alkylamino-lower alkoxy-2-lower alkanoyl, such as dimethylamino-lower alkoxyacetyl, or amino-, lower alkylamino or di-lower alkylamino-lower alkoxy-lower alkoxy-2-lower alkanoyl, such as dimethylamino- (2-lower alkoxyethoxy) acet means.
  • acylation can be carried out with acylating reagents using one of the methods below a) to e) or by one of the methods mentioned for protecting groups or by one of the im Organikum, 17th edition, VEB German Publishing House of Sciences, Berlin (East) 1988, procedures mentioned.
  • the etherification can be carried out with the alkylating agents mentioned above and among the same Reaction conditions take place, e.g. B. with diazomethane, alkyl halides, sulfonic acid esters, Sea wine salts, 1-substituted 3-aryltriazenes, etc.
  • reaction conditions known per se be carried out in the absence or usually presence of solvents or diluents, preferably those which are inert to the reagents used are and solve them, in the absence or presence of catalysts, condensing agents or neutralizing agents, depending on the type of reaction and / or reactants at reduced, normal or elevated temperature, e.g. in the temperature range from about -80 ° C to about 200 ° C, preferably from about -20 ° C to about 150 ° C, e.g. at room temperature up to the reflux temperature, with melts up to 220 ° C, under atmospheric pressure or in a closed vessel, if necessary under pressure, e.g. at the pressure in the reaction mixture under the reaction conditions occurs in a closed tube and / or in an inert atmosphere, e.g. under an argon or nitrogen atmosphere. They are preferably specific in each case mentioned reaction conditions.
  • Solvents and diluents are, for example, water, alcohols, e.g. Lower alkyl hydroxides, such as methanol, ethanol or propanol, diols, such as ethylene glycol, triols, such as Glycerin, or aryl alcohols such as phenol, acid amides, e.g. Carboxylic acid amides, such as dimethylformamide, Dimethylacetamide or 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) pyrimidinone (DMPU), or amides of inorganic acids, such as hexamethylphosphoric triamide, Ethers, e.g.
  • alcohols e.g. Lower alkyl hydroxides, such as methanol, ethanol or propanol
  • diols such as ethylene glycol
  • triols such as Glycerin
  • aryl alcohols such as phenol
  • acid amides e.g. Carboxylic acid
  • cyclic ethers such as tetrahydrofuran or dioxane, or acyclic ethers, such as Diethyl ether or ethylene glycol dimethyl ether, halogenated hydrocarbons, such as Halo lower alkanes, e.g. Methylene chloride or chloroform, ketones, such as acetone, nitriles, such as acetonitrile, acid anhydrides such as acetic anhydride, esters such as ethyl acetate, Bisalkanesulfines, such as dimethyl sulfoxide, nitrogen heterocycles, such as pyridine, hydrocarbons, e.g. Lower alkanes, such as heptane, or aromatics, such as benzene or toluene, or mixtures of these solvents, the most suitable solvents for the above reactions can be selected.
  • Halo lower alkanes e.g. Methylene chloride or chloroform
  • ketones such as acetone
  • the compounds, including their salts, can also be obtained in the form of hydrates or their crystals can e.g. the solvent used for crystallization lock in.
  • the invention also relates to those embodiments of the method in which one starts from a compound obtainable as an intermediate at any stage and takes the missing steps or terminates the process at any stage, or forms a starting material under the reaction conditions or in the form of a reactive Derivatives or salt used or one according to the inventive method available connection generated under the process conditions and processed in situ. It is preferable to start from those starting materials that belong to the Lead compounds that are described as preferred above.
  • the invention also relates to pharmaceutical preparations with compounds of the formula I. (these are called active ingredients).
  • the pharmacologically useful compounds of the present invention can e.g. B. used for the production of pharmaceutical preparations, which a effective amount of the active ingredient together or in admixture with a significant Amount of inorganic or organic, solid or liquid, pharmaceutical contain usable carriers.
  • the pharmaceutical preparations according to the invention are those for enteral, such as nasal, buccal, rectal or oral, or parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (humans and animals), which an effective dose of the pharmacological agent alone or with contain a significant amount of a pharmaceutically acceptable carrier.
  • enteral such as nasal, buccal, rectal or oral
  • parenteral such as intramuscular or intravenous, administration to warm-blooded animals (humans and animals)
  • the dosage of the active ingredient depends on the warm-blooded species, the body weight, age and individual condition, individual pharmacokinetic conditions, the disease to be treated and the mode of administration.
  • the invention also relates to pharmaceutical preparations and a method for treatment diseases caused by retroviruses, e.g. B. of AIDS, especially if HIV-1 or HIV-2 causes the disease, characterized by an antiretroviral effective amount of a compound of formula I according to the invention, in particular to a warm-blooded animal, e.g. B. People who, because of one of the diseases mentioned, in particular AIDS, which requires such treatment, is administered.
  • the on Warm-blooded animals, e.g. B. People of about 70 kg body weight to be administered dose amounts are between about 3 mg and about 10 g, preferably between about 10 mg and about 4 g, e.g. B. at about 25 mg to 2.0 g per person per day, distributed on preferably 1 to 5, in particular 1 to 3 individual doses, the z. B. can be the same size. Children are usually given half the dose of adults.
  • the pharmaceutical preparations contain from about 1% to about 95%, preferably from about 20% to about 90% of the active ingredient.
  • Pharmaceutical preparations according to the invention can e.g. B. in unit dose form, such as ampoules, vials, suppositories, dragées, tablets or capsules.
  • the pharmaceutical preparations of the present invention are known per se Way, e.g. B. by means of conventional solution, lyophilization, mixing, Granulating or Coating process.
  • Solutions of the active ingredient, and also suspensions, are preferably used or dispersions, in particular isotonic aqueous solutions, dispersions or suspensions, these z. B. in lyophilized preparations containing the active substance alone or together with a carrier material, e.g. B. Mannitol, included, before use can be produced.
  • the pharmaceutical preparations can be sterilized and / or auxiliary substances, e.g. B. preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, Salts to regulate osmotic pressure and / or buffers contain and are in a known manner, for. B. by means of conventional solution or Lyophilization process.
  • the solutions, dispersions or Suspensions can include viscosity-increasing substances such as sodium carboxymethyl cellulose, Carboxymethyl cellulose, dextran, polyvinyl pyrrolidone or gelatin.
  • Suspensions in oil contain, as an oily component, the vegetable, synthetic or semi-synthetic oils commonly used for injection purposes.
  • liquid fatty acid esters are to be mentioned, which as the acid component is a long-chain fatty acid with 8-22, in particular 12-22, carbon atoms, such as.
  • B. oleic acid, elaidic acid, erucic acid, brasidic acid or linoleic acid optionally with the addition of antioxidants, such as. B.
  • Vitamin E ⁇ -carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
  • the alcohol component of this fatty acid ester has a maximum of 6 carbon atoms and is a mono- or polyvalent, e.g. B. mono-, di- or trihydric alcohol, e.g. B. methanol, ethanol, propanol, butanol or pentanol or their isomers, but especially glycol and glycerin.
  • fatty acid esters for example: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375” (polyoxyethylene glycerol trioleate from Gattefossé, Paris), "Miglyol 812” (triglyceride of saturated fatty acids with chain length C 8 to C 12 from Hüls AG, Germany) , but especially vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and especially peanut oil.
  • injection preparations are produced in the usual way under sterile conditions, as well as filling in ampoules or vials and closing the containers.
  • compositions for oral use can be obtained by: the active ingredient combined with solid carriers, a mixture obtained if necessary granulated and, if desired or necessary, after the addition of suitable auxiliaries, processed into tablets, dragée kernels or capsules, or by producing Dispersions, preferably with phospholipids, which are filled into glasses.
  • suitable auxiliaries e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, ka
  • Suitable carriers are in particular fillers such as sugar, e.g. B. lactose, sucrose, Mannitol or sorbitol, cellulose preparations, and / or calcium phosphates, e.g. B. Tricalcium phosphate or calcium hydrogen phosphate, also binders, such as starch paste using e.g. B.
  • Flow regulators and lubricants e.g. B. silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol.
  • Dragée kernels will provided with suitable, possibly gastric juice-resistant coatings, one of the things concentrated sugar solutions, which may contain arabic gum, talc, polyvinylpyrrolidone, Contain polyethylene glycol and / or titanium dioxide, coating solutions in suitable organic solvents or, for the production of enteric Coatings, solutions of suitable cellulose preparations, such as ethyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate.
  • Capsules are plug-in capsules Gelatin and soft, closed capsules made of gelatin and a plasticizer, such as Glycerin or sorbitol. The capsules can contain the active ingredient in the form of granules, e.g. B.
  • Capsules are the active ingredient preferably in suitable oily auxiliaries, such as fatty oils, Paraffin oil or liquid polyethylene glycols, dissolved or suspended, also being Stabilizers and / or antibacterial agents can be added.
  • suitable oily auxiliaries such as fatty oils, Paraffin oil or liquid polyethylene glycols, dissolved or suspended, also being Stabilizers and / or antibacterial agents can be added.
  • the tablets or Dragée coatings and the capsule shells can contain dyes or pigments, e.g. B. for Identification or for labeling different doses of active ingredient.
  • the production process for these dispersions is characterized in that a solution or suspension of components a) and c) or a), b) and c), preferably of a) and b) in a weight ratio of 20: 1 to 1: 5, in particular from 5: 1 to 1 : 1, converted into a dispersion by dilution with water, then the organic solvents removed, for example by centrifugation, gel filtration, Ultrafiltration or in particular by dialysis, e.g. B.
  • tangential dialysis preferably against water, the dispersion obtained, preferably after addition of auxiliaries or Preservatives, if necessary setting an acceptable one pH by adding pharmaceutically acceptable buffers such as phosphate salts or organic acids (pure or dissolved in water), such as acetic acid or citric acid, preferably between pH 3 and 6, e.g. B. pH 4-5, if they are not already the right one Drug concentration has focused, preferably on a drug concentration from 2 to 30 mg / ml, in particular from 10 to 20 mg / ml, the concentration preferably by the latter methods for removing an organic Solvent takes place, in particular by ultrafiltration, for. B. using a Apparatus for performing tangential dialysis and ultrafiltration.
  • pharmaceutically acceptable buffers such as phosphate salts or organic acids (pure or dissolved in water), such as acetic acid or citric acid, preferably between pH 3 and 6, e.g. B. pH 4-5, if they are not already the right one Drug concentration has focused
  • the dispersion which can be prepared by this process and is stabilized by phospholipids is stable at room temperature for at least several hours, reproducible with regard to the Proportion of the components and toxicologically harmless and therefore in particular suitable for oral application in humans.
  • the order of magnitude of the particles obtained in the dispersion is variable and is preferably between about 1.0 x 10 -8 to about 1.0 x 10 -5 m, in particular between about 1 x 10 -7 and about 2 x 10 -6 m.
  • R A and R B with the meanings C 10-20 -acyl are preferably straight-chain C 10-20 -alkanoyl with an even number of carbon atoms and straight-chain C 10-20 -alkenoyl with one double bond and one even number of carbon atoms.
  • Straight-chain C 10-20 alkanoyl R A and R B with an even number of C atoms are, for example, n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl.
  • Straight-chain C 10-20 alkenoyl R A and R B with a double bond and an even number of C atoms are, for example, 6-cis, 6-trans, 9-cis or 9-trans-dodecenoyl, -tetradecenoyl, - hexadecenoyl, octadecenoyl or icosenoyl, especially 9-cis-octadecenoyl (oleoyl).
  • n is an integer from two to four, preferably two.
  • the group of the formula - (C n H 2n ) - represents unbranched or branched alkylene, for example 1,1-ethylene, 1,1-, 1,2- or 1,3-propylene or 1,2-, 1,3 - or 1,4-butylene.
  • Phospholipids of the formula A are, for example, naturally occurring cephalins in which R a , R b and R c are hydrogen or naturally occurring lecithins in which R a , R b and R c are methyl, for example cephaline or lecithin from soybeans, bovine brain, beef liver or chicken egg with different or identical acyl groups R A and R B or mixtures thereof.
  • Synthetic, essentially pure phospholipids of the formula A with different or identical acyl groups R A and R B are preferred.
  • synthetic phospholipid of the formula A defines phospholipids which have a uniform composition with respect to R A and R B.
  • Such synthetic phospholipids are preferably the lecithins and kephalins defined below, the acyl groups R A and R B of which have a defined structure and are derived from a defined fatty acid with a degree of purity higher than approximately 95%.
  • R A and R B can be the same or different and unsaturated or saturated.
  • naturally occurring phospholipids of the formula A defines phospholipids which have no uniform composition with respect to R A and R B.
  • natural phospholipids are also lecithins and cephalins, the acyl groups R A and R B of which are structurally indefinable and derived from naturally occurring fatty acid mixtures.
  • substantially pure phospholipid defines a level of purity of more than 70% (wt.) Of the phospholipid of the formula A, which is based on suitable Methods of determination, e.g. paper chromatographically, is detectable.
  • R A is straight-chain C 10-20 alkanoyl with an even number of carbon atoms
  • R B is straight-chain C 10-20 alkenoyl with one double bond and one have an even number of carbon atoms.
  • R a , R b and R c are methyl and n is two.
  • R A is n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl and R B is 9-cis-dodecenoyl, 9-cis-tetradecenoyl, 9-cis-hexadecenoyl, 9-cis -Octadecenoyl or 9-cis-icosenoyl.
  • R a , R b and R c are methyl and n is two.
  • a very particularly preferred phospholipid of the formula A is synthetic 1-n-hexadecanoyl-2- (9-cis-octadecenoyl) -3-sn-phosphatidylcholine with a purity of more than 95%.
  • Preferred natural, essentially pure phospholipids of the formula A are especially lecithin (L- ⁇ -phosphatidylcholine) from soybeans or chicken eggs.
  • phospholipids are preferably esters of phosphatidic acid (3-sn-phosphatidic acid) with the above-mentioned acyl radicals, such as phosphatidylserine and phosphatidylethanolamine.
  • Poorly soluble active ingredients can also be considered water-soluble, pharmaceutically acceptable Salts are present as defined above.
  • Components a), b) and c) or a) and c) are in the carrier liquid d) as Contain liposomes so that there are no solids or solid for several days to weeks Regenerate aggregates like micelles and the liquid with the named Components, optionally after filtration, preferably orally, can be applied.
  • non-toxic auxiliaries can be contained in the carrier liquid d) be included, e.g. water-soluble excipients used for the production of isotonic Conditions are suitable, e.g. ionic additives such as table salt or nonionic Additives (scaffolders) such as sorbitol, mannitol or glucose or water-soluble Stabilizers for liposome dispersion such as lactose, fructose or sucrose.
  • ionic additives such as table salt or nonionic Additives (scaffolders) such as sorbitol, mannitol or glucose or water-soluble Stabilizers for liposome dispersion such as lactose, fructose or sucrose.
  • liquid can be used in the carrier liquid
  • emulsifiers such as oleic acid, nonionic surfactants of the fatty acid polyhydroxy alcohol ester type such as sorbitan monolaurate, oleate, stearate or palmitate, Sorbitan tristearate or trioleate, polyoxyethylene adducts of fatty acid polyhydroxy alcohol esters such as polyoxyethylene sorbitan monolaurate, oleate, stearate, palmitate, tristearate or trioleate, polyethylene glycol fatty acid esters such as polyoxyethyl stearate, polyethylene glycol 400 stearate, Polyethylene glycol 2000 stearate, especially ethylene oxide propylene oxide Block polymers of the type Pluronic® (Wyandotte Chem. Corp.) or Synperonic® (ICI).
  • Preferred preservatives are e.g. B. antioxidants such as ascorbic acid, or Microbicides, such as sorbic acid or benzoic acid.
  • R f (A) means, for example, that the R f value was determined in solvent system A.
  • Mass spectroscopic measurements are obtained either by conventional MS or according to the "Fast Atom Bombardment” (FAB-MS) method.
  • the mass data in the first case relate to the unprotonated molecular ion (M) + or the protonated molecular ion (M + H) + .
  • the starting materials are made as follows:
  • the title compound can also be prepared by (analogously to EP 0 432 695, published on June 19, 1991, Example 3) a solution of N- (2-quinolylcarbonyl- M8M L-asparagine and N-tert-butyl-decahydro- 2- [2 (R) -hydroxy-4-phenyl-3 (S) -aminobutyl] - (4aS, 8aS) -isoquinoline-3 (S) -carboxamide (prepared as described in the alternative process under 1 b)) in tetrahydrofuran on - is cooled 10 ° C and 3-hydroxy-1,2,3-benzotriazin-4 (3H) -one (Fluka, Switzerland) and dicyclohexylcarbodiimide is added, the mixture at said temperature for 2 h and at 20 0 C for an additional 16 h, then diluted with ethyl acetate and filtered. The filtrate is then washed with saturated sodium bicarbonate
  • a sterile-filtered aqueous solution of one of the compounds of the formula I mentioned in the preceding Examples 1 to 7, which additionally contains 20% cyclodextrin, and a sterile gelatin solution preserved with phenol are mixed under heating under aseptic conditions so that 1.0 ml of the solution follows Composition results: Active ingredient 3 mg gelatin 150.0 mg phenol 4.7 mg least Water with 20% cyclodextrins 1.0 ml
  • the following components are processed to produce 10,000 tablets containing 100 mg of compound of the formula I: Active ingredient 1000 g Cornstarch 680 g Colloidal silica 200 g Magnesium stearate 20 g Stearic acid 50 g Sodium carboxymethyl starch 250 g water quantum satis
  • Example 12 Orally Administerable Dispersion 1
  • the ethanol is removed from the mixture by tangential dialysis ("cross flow filtration") against 1750 ml of water (system: Minitan®, 700 cm 2 - polyethersulphone membrane with an exclusion limit of 100 kD, from Millipore (USA)).
  • the mixture is concentrated to 15 mg of active ingredient by ultrafiltration using the same system.
  • the dispersion is again concentrated to 15 mg / ml and filled into glasses, for example with 20 ml content.
  • the dispersion particles have a diameter of 0.1 - 2 ⁇ m. They are stable at +2 to 8 ° C for at least half a year and are suitable for oral administration.
  • the preparation is carried out analogously to Example 12, but using 25 mg of Compound of formula I and 50 mg POPC for the preparation of the ethanolic solution.
  • the preparation is carried out analogously to Example 12, but using 25 mg of Compound of formula I and 125 mg POPC for the preparation of the ethanolic solution.
  • the preparation is carried out analogously to Example 12, but using 50 mg of Compound of formula I and 50 mg POPC for the preparation of the ethanolic solution.
  • the preparation is carried out analogously to one of Examples 12 to 15, but using of the compound of formula I and phosphatidylcholine from soy or phosphatidylcholine from egg yolk (70 - 100% pure) instead of POPC for the production of ethanol Solution.
  • an antioxidant such as ascorbic acid is used in a concentration of 5 mg / ml added.

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US6008228A (en) * 1995-06-06 1999-12-28 Hoffman-La Roche Inc. Pharmaceutical compositions containing proteinase inhibitors
US6436989B1 (en) 1997-12-24 2002-08-20 Vertex Pharmaceuticals, Incorporated Prodrugs of aspartyl protease inhibitors
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